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12 pages, 1303 KiB

Open AccessArticle

Targeted Induction of Endogenous VDUP1 by Small Activating RNA Inhibits the Growth of Lung Cancer Cells

by Ki Hwan Park, Jeong-Wook Yang, Joo-Hee Kwon, Hyunju Lee, Yeo Dae Yoon, Byeong Jo Choi, Myeong Youl Lee, Chang Woo Lee, Sang-Bae Han and Jong Soon Kang

Int. J. Mol. Sci. 2022, 23(14), 7743; https://doi.org/10.3390/ijms23147743 - 13 Jul 2022

Cited by 6 | Viewed by 2195

Abstract

Recent studies have reported that small double-strand RNAs (dsRNAs) can activate endogenous genes via an RNA-based promoter targeting mechanism termed RNA activation (RNAa). In the present study, we showed that dsVDUP1-834, a novel small activating RNA (saRNA) targeting promoter of vitamin D₃ [...] Read more.

Recent studies have reported that small double-strand RNAs (dsRNAs) can activate endogenous genes via an RNA-based promoter targeting mechanism termed RNA activation (RNAa). In the present study, we showed that dsVDUP1-834, a novel small activating RNA (saRNA) targeting promoter of vitamin D₃ up-regulated protein 1 (VDUP1) gene, up-regulated expression of VDUP1 at both mRNA and protein levels in A549 lung cancer cells. We also demonstrated that dsVDUP1-834 inhibited cell proliferation in A549 lung cancer cells. Further studies showed that dsVDUP1-834 induced cell-cycle arrest by increasing p27 and p53 and decreasing cyclin A and cyclin B1. In addition, knockdown of VDUP1 abrogated dsVDUP1-834-induced up-regulation of VDUP1 gene expression and related effects. The activation of VDUP1 by dsVDUP1-834 was accompanied by an increase in dimethylation of histone 3 at lysine 4 (H3K4me2) and acetylation of histone 3 (H3ac) and a decrease in dimethylation of histone 3 at lysine 9 (H3K9me2) at the target site of VDUP1 promoter. Moreover, the enrichment of Ago2 was detected at the dsVDUP1-834 target site, and Ago2 knockdown significantly suppressed dsVDUP1-834-mediated inhibition of cell proliferation and modulation of cell-cycle regulators. Taken together, the results presented in this report demonstrate that dsVDUP1-834 induces VDUP1 gene expression by epigenetic changes, resulting in cell growth inhibition and cell-cycle arrest. Our results suggest that targeted induction of VDUP1 by dsVDUP1-834 might be a promising therapeutic strategy for the treatment of lung cancer. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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23 pages, 7241 KiB

Open AccessArticle

c-Myc Protein Level Affected by Unsymmetrical Bisacridines Influences Apoptosis and Senescence Induced in HCT116 Colorectal and H460 Lung Cancer Cells

by Monika Pawłowska, Jolanta Kulesza and Ewa Augustin

Int. J. Mol. Sci. 2022, 23(6), 3061; https://doi.org/10.3390/ijms23063061 - 11 Mar 2022

Cited by 7 | Viewed by 2762

Abstract

Unsymmetrical bisacridines (UAs) are highly active antitumor compounds. They contain in their structure the drugs previously synthesized in our Department: C-1311 and C-1748. UAs exhibit different properties than their monomer components. They do not intercalate to dsDNA but stabilize the G-quadruplex structures, particularly [...] Read more.

Unsymmetrical bisacridines (UAs) are highly active antitumor compounds. They contain in their structure the drugs previously synthesized in our Department: C-1311 and C-1748. UAs exhibit different properties than their monomer components. They do not intercalate to dsDNA but stabilize the G-quadruplex structures, particularly those of the MYC and KRAS genes. Since MYC and KRAS are often mutated and constitutively expressed in cancer cells, they can be used as therapeutic targets. Herein, we investigate whether UAs can affect the expression and protein level of c-Myc and K-Ras in HCT116 and H460 cancer cells, and if so, what are the consequences for the UAs-induced cellular response. UAs did not affect K-Ras, but they strongly influenced the expression and translation of the c-Myc protein, and in H460 cells, they caused its full inhibition. UAs treatment resulted in apoptosis, as confirmed by the morphological changes, the presence of sub-G1 population and active caspase-3, cleaved PARP, annexin-V/PI staining and a decrease in mitochondrial potential. Importantly, apoptosis was induced earlier and to a greater extent in H460 compared to HCT116 cells. Moreover, accelerated senescence occurred only in H460 cells. In conclusion, the strong inhibition of c-Myc by UAs in H460 cells may participate in the final cellular response (apoptosis, senescence). Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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24 pages, 6926 KiB

Open AccessArticle

Antibody Conjugated PLGA Nanocarriers and Superparmagnetic Nanoparticles for Targeted Delivery of Oxaliplatin to Cells from Colorectal Carcinoma

by Alma Lucia Villela Zumaya, Silvie Rimpelová, Markéta Štějdířová, Pavel Ulbrich, Jarmila Vilčáková and Fatima Hassouna

Int. J. Mol. Sci. 2022, 23(3), 1200; https://doi.org/10.3390/ijms23031200 - 21 Jan 2022

Cited by 24 | Viewed by 5041

Abstract

Anti-CD133 monoclonal antibody (Ab)-conjugated poly(lactide-co-glycolide) (PLGA) nanocarriers, for the targeted delivery of oxaliplatin (OXA) and superparamagnetic nanoparticles (IO-OA) to colorectal cancer cells (CaCo-2), were designed, synthesized, characterized, and evaluated in this study. The co-encapsulation of OXA and IO-OA was achieved in two types [...] Read more.

Anti-CD133 monoclonal antibody (Ab)-conjugated poly(lactide-co-glycolide) (PLGA) nanocarriers, for the targeted delivery of oxaliplatin (OXA) and superparamagnetic nanoparticles (IO-OA) to colorectal cancer cells (CaCo-2), were designed, synthesized, characterized, and evaluated in this study. The co-encapsulation of OXA and IO-OA was achieved in two types of polymeric carriers, namely, PLGA and poly(lactide-co-glycolide)-poly(ethylene glycol) (PLGA-PEG) by double emulsion. PLGA_IO-OA_OXA and PEGylated PLGA_IO-OA_OXA nanoparticles displayed a comparable mean diameter of 207 ± 70 nm and 185 ± 119 nm, respectively. The concentration of the released OXA from the PEGylated PLGA_IO-OA_OXA increased very rapidly, reaching ~100% release after only 2 h, while the PLGA_IO-OA_OXA displayed a slower and sustained drug release. Therefore, for a controlled OXA release, non-PEGylated PLGA nanoparticles were more convenient. Interestingly, preservation of the superparamagnetic behavior of the IO-OA, without magnetic hysteresis all along the dissolution process, was observed. The non-PEGylated nanoparticles (PLGA_OXA, PLGA_IO-OA_OXA) were selected for the anti-CD133 Ab conjugation. The affinity of Ab-coated nanoparticles for CD133-positive cells was examined using fluorescence microscopy in CaCo-2 cells, which was followed by a viability assay. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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24 pages, 6560 KiB

Open AccessArticle

Dynophore-Based Approach in Virtual Screening: A Case of Human DNA Topoisomerase IIα

by Matej Janežič, Katja Valjavec, Kaja Bergant Loboda, Barbara Herlah, Iza Ogris, Mirijam Kozorog, Marjetka Podobnik, Simona Golič Grdadolnik, Gerhard Wolber and Andrej Perdih

Int. J. Mol. Sci. 2021, 22(24), 13474; https://doi.org/10.3390/ijms222413474 - 15 Dec 2021

Cited by 12 | Viewed by 3430

Abstract

In this study, we utilized human DNA topoisomerase IIα as a model target to outline a dynophore-based approach to catalytic inhibitor design. Based on MD simulations of a known catalytic inhibitor and the native ATP ligand analog, AMP-PNP, we derived a joint dynophore [...] Read more.

In this study, we utilized human DNA topoisomerase IIα as a model target to outline a dynophore-based approach to catalytic inhibitor design. Based on MD simulations of a known catalytic inhibitor and the native ATP ligand analog, AMP-PNP, we derived a joint dynophore model that supplements the static structure-based-pharmacophore information with a dynamic component. Subsequently, derived pharmacophore models were employed in a virtual screening campaign of a library of natural compounds. Experimental evaluation identified flavonoid compounds with promising topoisomerase IIα catalytic inhibition and binding studies confirmed interaction with the ATPase domain. We constructed a binding model through docking and extensively investigated it with molecular dynamics MD simulations, essential dynamics, and MM-GBSA free energy calculations, thus reconnecting the new results to the initial dynophore-based screening model. We not only demonstrate a new design strategy that incorporates a dynamic component of molecular recognition, but also highlight new derivates in the established flavonoid class of topoisomerase II inhibitors. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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11 pages, 1785 KiB

Open AccessArticle

YES1 as a Therapeutic Target for HER2-Positive Breast Cancer after Trastuzumab and Trastuzumab-Emtansine (T-DM1) Resistance Development

by Miwa Fujihara, Tadahiko Shien, Kazuhiko Shien, Ken Suzawa, Tatsuaki Takeda, Yidan Zhu, Tomoka Mamori, Yusuke Otani, Ryo Yoshioka, Maya Uno, Yoko Suzuki, Yuko Abe, Minami Hatono, Takahiro Tsukioki, Yuko Takahashi, Mariko Kochi, Takayuki Iwamoto, Naruto Taira, Hiroyoshi Doihara and Shinichi Toyooka

Int. J. Mol. Sci. 2021, 22(23), 12809; https://doi.org/10.3390/ijms222312809 - 26 Nov 2021

Cited by 7 | Viewed by 3294

Abstract

Trastuzumab-emtansine (T-DM1) is a therapeutic agent molecularly targeting human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it is especially effective for MBC with resistance to trastuzumab. Although several reports have described T-DM1 resistance, few have examined the mechanism underlying [...] Read more.

Trastuzumab-emtansine (T-DM1) is a therapeutic agent molecularly targeting human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it is especially effective for MBC with resistance to trastuzumab. Although several reports have described T-DM1 resistance, few have examined the mechanism underlying T-DM1 resistance after the development of acquired resistance to trastuzumab. We previously reported that YES1, a member of the Src family, plays an important role in acquired resistance to trastuzumab in HER2-amplified breast cancer cells. We newly established a trastuzumab/T-DM1-dual-resistant cell line and analyzed the resistance mechanisms in this cell line. At first, the T-DM1 effectively inhibited the YES1-amplified trastuzumab-resistant cell line, but resistance to T-DM1 gradually developed. YES1 amplification was further enhanced after acquired resistance to T-DM1 became apparent, and the knockdown of the YES1 or the administration of the Src inhibitor dasatinib restored sensitivity to T-DM1. Our results indicate that YES1 is also strongly associated with T-DM1 resistance after the development of acquired resistance to trastuzumab, and the continuous inhibition of YES1 is important for overcoming resistance to T-DM1. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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13 pages, 4080 KiB

Open AccessCommunication

PD-L1 Inhibitors: Different Classes, Activities, and Mechanisms of Action

by Ewa Surmiak, Katarzyna Magiera-Mularz, Bogdan Musielak, Damian Muszak, Justyna Kocik-Krol, Radoslaw Kitel, Jacek Plewka, Tad A. Holak and Lukasz Skalniak

Int. J. Mol. Sci. 2021, 22(21), 11797; https://doi.org/10.3390/ijms222111797 - 30 Oct 2021

Cited by 22 | Viewed by 4309

Abstract

Targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) interaction has become an established strategy for cancer immunotherapy. Although hundreds of small-molecule, peptide, and peptidomimetic inhibitors have been proposed in recent years, only a limited number of drug candidates [...] Read more.

Targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) interaction has become an established strategy for cancer immunotherapy. Although hundreds of small-molecule, peptide, and peptidomimetic inhibitors have been proposed in recent years, only a limited number of drug candidates show good PD-1/PD-L1 blocking activity in cell-based assays. In this article, we compare representative molecules from different classes in terms of their PD-1/PD-L1 dissociation capacity measured by HTRF and in vitro bioactivity determined by the immune checkpoint blockade (ICB) co-culture assay. We point to recent discoveries that underscore important differences in the mechanisms of action of these molecules and also indicate one principal feature that needs to be considered, which is the eventual human PD-L1 specificity. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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22 pages, 3928 KiB

Open AccessArticle

Fluoroquinolones Suppress TGF-β and PMA-Induced MMP-9 Production in Cancer Cells: Implications in Repurposing Quinolone Antibiotics for Cancer Treatment

by Cheng-Yi Huang, Jenq-Lin Yang, Jih-Jung Chen, Shun-Ban Tai, Yu-Hsuan Yeh, Pei-Feng Liu, Ming-Wei Lin, Chih-Ling Chung and Chun-Lin Chen

Int. J. Mol. Sci. 2021, 22(21), 11602; https://doi.org/10.3390/ijms222111602 - 27 Oct 2021

Cited by 10 | Viewed by 3200

Abstract

Background: Fluoroquinolones (FQs) are potent antimicrobials with multiple effects on host cells and tissues. Although FQs can attenuate cancer invasion and metastasis, the underlying molecular mechanisms remain unclear. Matrix metalloproteinase-9 (MMP-9) has functional roles in tumor angiogenesis, invasion, and metastasis, and is associated [...] Read more.

Background: Fluoroquinolones (FQs) are potent antimicrobials with multiple effects on host cells and tissues. Although FQs can attenuate cancer invasion and metastasis, the underlying molecular mechanisms remain unclear. Matrix metalloproteinase-9 (MMP-9) has functional roles in tumor angiogenesis, invasion, and metastasis, and is associated with cancer progression and poor prognosis, suggesting that inhibitors of MMP-9 activity and transcription are prime candidates for cancer therapy. Despite numerous preclinical data supporting the use of MMP-9 inhibitors as anticancer drugs, the few available examples are not therapeutically useful due to low specificity and off-target effects. We examined the effects of FQs on MMP-9 production in cancer cells following transforming growth factor beta (TGF-β) and phorbol 12-myristate 13-acetate (PMA) stimulation. Experimental approaches: Using confluent cultures of HepG2 and A549 cells, the effects of FQs (ciprofloxacin, levofloxacin, clinafloxacin, gatifloxacin, and enrofloxacin) on TGF-β and PMA-induced MMP-9 mRNA expression and production were studied in RNA extracts and culture supernatants, respectively. FQs specifically abrogated TGF-β and PMA-induced MMP-9 levels and activity in a concentration and time-dependent manner, without affecting other MMPs or proteins involved in epithelial-mesenchymal transition. Additionally, FQs inhibited TGF-β and PMA-induced cell migration via p38 and cyclic AMP signaling pathways. Conclusions and implications: Overall, we demonstrated that FQs inhibit cancer cell migration and invasion by downregulating MMP-9 expression and revealed the cellular mechanisms underlying their potential value in cancer treatment. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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20 pages, 78177 KiB

Open AccessArticle

Inhibition of Mitochondrial Metabolism Leads to Selective Eradication of Cells Adapted to Acidic Microenvironment

by Martina Koncošová, Nikola Vrzáčková, Ivana Křížová, Petra Tomášová, Silvie Rimpelová, Aleš Dvořák, Libor Vítek, Michaela Rumlová, Tomáš Ruml and Jaroslav Zelenka

Int. J. Mol. Sci. 2021, 22(19), 10790; https://doi.org/10.3390/ijms221910790 - 6 Oct 2021

Cited by 8 | Viewed by 3430

Abstract

Metabolic transformation of cancer cells leads to the accumulation of lactate and significant acidification in the tumor microenvironment. Both lactate and acidosis have a well-documented impact on cancer progression and negative patient prognosis. Here, we report that cancer cells adapted to acidosis are [...] Read more.

Metabolic transformation of cancer cells leads to the accumulation of lactate and significant acidification in the tumor microenvironment. Both lactate and acidosis have a well-documented impact on cancer progression and negative patient prognosis. Here, we report that cancer cells adapted to acidosis are significantly more sensitive to oxidative damage induced by hydrogen peroxide, high-dose ascorbate, and photodynamic therapy. Higher lactate concentrations abrogate the sensitization. Mechanistically, acidosis leads to a drop in antioxidant capacity caused by a compromised supply of nicotinamide adenine dinucleotide phosphate (NADPH) derived from glucose metabolism. However, lactate metabolism in the Krebs cycle restores NADPH supply and antioxidant capacity. CPI-613 (devimistat), an anticancer drug candidate, selectively eradicates the cells adapted to acidosis through inhibition of the Krebs cycle and induction of oxidative stress while completely abrogating the protective effect of lactate. Simultaneous cell treatment with tetracycline, an inhibitor of the mitochondrial proteosynthesis, further enhances the cytotoxic effect of CPI-613 under acidosis and in tumor spheroids. While there have been numerous attempts to treat cancer by neutralizing the pH of the tumor microenvironment, we alternatively suggest considering tumor acidosis as the Achilles’ heel of cancer as it enables selective therapeutic induction of lethal oxidative stress. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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17 pages, 3188 KiB

Open AccessArticle

RORα Suppresses Cancer-Associated Inflammation by Repressing Respiratory Complex I-Dependent ROS Generation

by Wei Mao, Gaofeng Xiong, Yuanyuan Wu, Chi Wang, Daret St. Clair, Jia-Da Li and Ren Xu

Int. J. Mol. Sci. 2021, 22(19), 10665; https://doi.org/10.3390/ijms221910665 - 1 Oct 2021

Cited by 19 | Viewed by 2991

Abstract

Breast cancer development is associated with macrophage infiltration and differentiation in the tumor microenvironment. Our previous study highlights the crucial function of reactive oxygen species (ROS) in enhancing macrophage infiltration during the disruption of mammary tissue polarity. However, the regulation of ROS and [...] Read more.

Breast cancer development is associated with macrophage infiltration and differentiation in the tumor microenvironment. Our previous study highlights the crucial function of reactive oxygen species (ROS) in enhancing macrophage infiltration during the disruption of mammary tissue polarity. However, the regulation of ROS and ROS-associated macrophage infiltration in breast cancer has not been fully determined. Previous studies identified retinoid orphan nuclear receptor alpha (RORα) as a potential tumor suppressor in human breast cancer. In the present study, we showed that retinoid orphan nuclear receptor alpha (RORα) significantly decreased ROS levels and inhibited ROS-mediated cytokine expression in breast cancer cells. RORα expression in mammary epithelial cells inhibited macrophage infiltration by repressing ROS generation in the co-culture assay. Using gene co-expression and chromatin immunoprecipitation (ChIP) analyses, we identified complex I subunits NDUFS6 and NDUFA11 as RORα targets that mediated its function in suppressing superoxide generation in mitochondria. Notably, the expression of RORα in 4T1 cells significantly inhibited cancer metastasis, reduced macrophage accumulation, and enhanced M1-like macrophage differentiation in tumor tissue. In addition, reduced RORα expression in breast cancer tissue was associated with an increased incidence of cancer metastasis. These results provide additional insights into cancer-associated inflammation, and identify RORα as a potential target to suppress ROS-induced mammary tumor progression. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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20 pages, 6433 KiB

Open AccessArticle

Synergistic Effect of Simultaneous versus Sequential Combined Treatment of Histone Deacetylase Inhibitor Valproic Acid with Etoposide on Melanoma Cells

by Yueh-Ming Shyu, Lawrence Yu-Min Liu and Yung-Jen Chuang

Int. J. Mol. Sci. 2021, 22(18), 10029; https://doi.org/10.3390/ijms221810029 - 17 Sep 2021

Cited by 4 | Viewed by 2753

Abstract

Melanoma is the most lethal form of skin cancer, which is intrinsically resistant to conventional chemotherapy. Combination therapy has been developed to overcome this challenge and show synergistic anticancer effects on melanoma. Notably, the histone deacetylase inhibitor, valproic acid (VPA), has been indicated [...] Read more.

Melanoma is the most lethal form of skin cancer, which is intrinsically resistant to conventional chemotherapy. Combination therapy has been developed to overcome this challenge and show synergistic anticancer effects on melanoma. Notably, the histone deacetylase inhibitor, valproic acid (VPA), has been indicated as a potential sensitizer of chemotherapy drugs on various metastatic cancers, including advanced melanoma. In this study, we explored whether VPA could serve as an effective sensitizer of chemotherapy drug etoposide (ETO) on B16-F10 and SK-MEL-2-Luc melanoma cell lines in response to drug-induced DNA damages. Our results demonstrated that the VPA-ETO simultaneous combined treatment and ETO pretreated sequential combined treatment generated higher inhibitory effectivities than the individual treatment of each drug. We found the VPA-ETO simultaneous combined treatment contributed to the synergistic inhibitory effect by the augmented DNA double-strand breaks, accompanied by a compromised homologous recombination activity. In comparison, the ETO pretreated sequential combined treatment led to synergistic inhibitory effect via enhanced apoptosis. Surprisingly, the enhanced homologous recombination activity and G2/M phase arrest resulted in the antagonistic effect in both cells under VPA pretreated sequential combined treatment. In summary, our findings suggested that sequential order and effective dose of drug administration in VPA-ETO combination therapy could induce different cellular responses in melanoma cells. Such understanding might help potentiate the effectiveness of melanoma treatment and highlight the importance of sequential order and effective dose in combination therapy. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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17 pages, 3724 KiB

Open AccessArticle

9-O-Terpenyl-Substituted Berberrubine Derivatives Suppress Tumor Migration and Increase Anti-Human Non-Small-Cell Lung Cancer Activity

by Jia-Ming Chang, Jin-Yi Wu, Shu-Hsin Chen, Wen-Ying Chao, Hsiang-Hao Chuang, Kam-Hong Kam, Pei-Wen Zhao, Yi-Zhen Li, Yu-Pei Yen and Ying-Ray Lee

Int. J. Mol. Sci. 2021, 22(18), 9864; https://doi.org/10.3390/ijms22189864 - 13 Sep 2021

Cited by 7 | Viewed by 2495

Abstract

Lung cancer is one of the most common cancers and the leading cause of death in humans worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases and is often diagnosed at a late stage. Among patients with NSCLC, 50% [...] Read more.

Lung cancer is one of the most common cancers and the leading cause of death in humans worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases and is often diagnosed at a late stage. Among patients with NSCLC, 50% die within 1 year after diagnosis. Even with clinical intervention, the 5-year survival rate is only approximately 20%. Therefore, the development of an advanced therapeutic strategy or novel agent is urgently required for treating NSCLC. Berberine exerts therapeutic activity toward NSCLC; therefore, its activity as an antitumor agent needs to be explored further. In this study, three terpenylated-bromide derivatives of berberrubine were synthesized and their anti-NSCLC activities were evaluated. Each derivative had higher anti-NSCLCs activity than berberrubine and berberine. Among them, 9-O-gernylberberrubine bromide (B4) and 9-O-farnesylberberrubine bromide (B5) showed greater growth inhibition, cell-cycle regulation, in vitro tumorigenesis suppression, and tumor migration reduction. In addition, some degree of apoptosis and autophagic flux blocking was noted in the cells under B4 and B5 treatments. Our study demonstrates that the berberrubine derivatives, B4 and B5, exhibit impressive anti-NSCLC activities and have potential for use as chemotherapeutic agents against NSCLC. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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15 pages, 5072 KiB

Open AccessArticle

Competing Endogenous RNA of Snail and Zeb1 UTR in Therapeutic Resistance of Colorectal Cancer

by Nam Hee Kim, Sang Hyun Song, Yun Hee Choi, Kyu Ho Hwang, Jun Seop Yun, Hyeeun Song, So Young Cha, Sue Bean Cho, Inhan Lee, Hyun Sil Kim and Jong In Yook

Int. J. Mol. Sci. 2021, 22(17), 9589; https://doi.org/10.3390/ijms22179589 - 3 Sep 2021

Cited by 8 | Viewed by 2723

Abstract

The epithelial-mesenchymal transition (EMT) comprises an important biological mechanism not only for cancer progression but also in the therapeutic resistance of cancer cells. While the importance of the protein abundance of EMT-inducers, such as Snail (SNAI1) and Zeb1 (ZEB1), during EMT progression is [...] Read more.

The epithelial-mesenchymal transition (EMT) comprises an important biological mechanism not only for cancer progression but also in the therapeutic resistance of cancer cells. While the importance of the protein abundance of EMT-inducers, such as Snail (SNAI1) and Zeb1 (ZEB1), during EMT progression is clear, the reciprocal interactions between the untranslated regions (UTRs) of EMT-inducers via a competing endogenous RNA (ceRNA) network have received little attention. In this study, we found a synchronized transcript abundance of Snail and Zeb1 mediated by a non-coding RNA network in colorectal cancer (CRC). Importantly, the trans-regulatory ceRNA network in the UTRs of EMT inducers is mediated by competition between tumor suppressive miRNA-34 (miR-34) and miRNA-200 (miR-200). Furthermore, the ceRNA network consisting of the UTRs of EMT inducers and tumor suppressive miRs is functional in the EMT phenotype and therapeutic resistance of colon cancer. In The Cancer Genome Atlas (TCGA) samples, we also found genome-wide ceRNA gene sets regulated by miR-34a and miR-200 in colorectal cancer. These results indicate that the ceRNA networks regulated by the reciprocal interaction between EMT gene UTRs and tumor suppressive miRs are functional in CRC progression and therapeutic resistance. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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16 pages, 3562 KiB

Open AccessArticle

Identification and Validation of Esophageal Squamous Cell Carcinoma Targets for Fluorescence Molecular Endoscopy

by Xiaojuan Zhao, Qingfeng Huang, Marjory Koller, Matthijs D. Linssen, Wouter T. R. Hooghiemstra, Steven J. de Jongh, Marcel A. T. M. van Vugt, Rudolf S. N. Fehrmann, Enmin Li and Wouter B. Nagengast

Int. J. Mol. Sci. 2021, 22(17), 9270; https://doi.org/10.3390/ijms22179270 - 27 Aug 2021

Cited by 4 | Viewed by 3566

Abstract

Dysplasia and intramucosal esophageal squamous cell carcinoma (ESCC) frequently go unnoticed with white-light endoscopy and, therefore, progress to invasive tumors. If suitable targets are available, fluorescence molecular endoscopy might be promising to improve early detection. Microarray expression data of patient-derived normal esophagus ( [...] Read more.

Dysplasia and intramucosal esophageal squamous cell carcinoma (ESCC) frequently go unnoticed with white-light endoscopy and, therefore, progress to invasive tumors. If suitable targets are available, fluorescence molecular endoscopy might be promising to improve early detection. Microarray expression data of patient-derived normal esophagus (n = 120) and ESCC samples (n = 118) were analyzed by functional genomic mRNA (FGmRNA) profiling to predict target upregulation on protein levels. The predicted top 60 upregulated genes were prioritized based on literature and immunohistochemistry (IHC) validation to select the most promising targets for fluorescent imaging. By IHC, GLUT1 showed significantly higher expression in ESCC tissue (30 patients) compared to the normal esophagus adjacent to the tumor (27 patients) (p < 0.001). Ex vivo imaging of GLUT1 with the 2-DG 800CW tracer showed that the mean fluorescence intensity in ESCC (n = 17) and high-grade dysplasia (HGD, n = 13) is higher (p < 0.05) compared to that in low-grade dysplasia (LGD) (n = 7) and to the normal esophagus adjacent to the tumor (n = 5). The sensitivity and specificity of 2-DG 800CW to detect HGD and ESCC is 80% and 83%, respectively (ROC = 0.85). We identified and validated GLUT1 as a promising molecular imaging target and demonstrated that fluorescent imaging after topical application of 2-DG 800CW can differentiate HGD and ESCC from LGD and normal esophagus. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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16 pages, 3626 KiB

Open AccessArticle

Gain-of-Function Mutant TP53 R248Q Overexpressed in Epithelial Ovarian Carcinoma Alters AKT-Dependent Regulation of Intercellular Trafficking in Responses to EGFR/MDM2 Inhibitor

by Zih-Yin Lai, Kai-Yun Tsai, Shing-Jyh Chang and Yung-Jen Chuang

Int. J. Mol. Sci. 2021, 22(16), 8784; https://doi.org/10.3390/ijms22168784 - 16 Aug 2021

Cited by 6 | Viewed by 2937

Abstract

As the most common gene mutation found in cancers, p53 mutations are detected in up to 96% of high-grade serous ovarian carcinoma (HGSOC). Meanwhile, mutant p53 overexpression is known to drive oncogenic phenotypes in cancer patients and to sustain the activation of EGFR [...] Read more.

As the most common gene mutation found in cancers, p53 mutations are detected in up to 96% of high-grade serous ovarian carcinoma (HGSOC). Meanwhile, mutant p53 overexpression is known to drive oncogenic phenotypes in cancer patients and to sustain the activation of EGFR signaling. Previously, we have demonstrated that the combined inhibition of EGFR and MDM2-p53 pathways, by gefitinib and JNJ-26854165, exerts a strong synergistic lethal effect on HGSOC cells. In this study, we investigated whether the gain-of-function p53 mutation (p53^R248Q) overexpression could affect EGFR-related signaling and the corresponding drug inhibition outcome in HGSOC. The targeted inhibition responses of gefitinib and JNJ-26854165, in p53^R248Q-overexpressing cells, were extensively evaluated. We found that the phosphorylation of AKT increased when p53^R248Q was transiently overexpressed. Immunocytochemistry analysis further showed that upon p53^R248Q overexpression, several AKT-related regulatory proteins translocated in unique intracellular patterns. Subsequent analysis revealed that, under the combined inhibition of gefitinib and JNJ-26854165, the cytonuclear trafficking of EGFR and MDM2 was disrupted. Next, we analyzed the gefitinib and JNJ-26854165 responses and found differential sensitivity to the single- or combined-drug inhibitions in p53^R248Q-overexpressing cells. Our findings suggested that the R248Q mutation of p53 in HGSOC caused significant changes in signaling protein function and trafficking, under EGFR/MDM2-targeted inhibition. Such knowledge could help to advance our understanding of the role of mutant p53 in ovarian carcinoma and to improve the prognosis of patients receiving EGFR/MDM2-targeted therapies. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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22 pages, 15071 KiB

Open AccessArticle

Novel N-Substituted Amino Acid Hydrazone-Isatin Derivatives: Synthesis, Antioxidant Activity, and Anticancer Activity in 2D and 3D Models In Vitro

by Ingrida Tumosienė, Ilona Jonuškienė, Kristina Kantminienė, Vytautas Mickevičius and Vilma Petrikaitė

Int. J. Mol. Sci. 2021, 22(15), 7799; https://doi.org/10.3390/ijms22157799 - 21 Jul 2021

Cited by 22 | Viewed by 3139

Abstract

A series of novel mono and bishydrazones each bearing a 2-oxindole moiety along with substituted phenylaminopropanamide, pyrrolidin-2-one, benzimidazole, diphenylmethane, or diphenylamine fragments were synthesized, and their anticancer activities were tested by MTT assay against human melanoma A375 and colon adenocarcinoma HT-29 cell lines. [...] Read more.

A series of novel mono and bishydrazones each bearing a 2-oxindole moiety along with substituted phenylaminopropanamide, pyrrolidin-2-one, benzimidazole, diphenylmethane, or diphenylamine fragments were synthesized, and their anticancer activities were tested by MTT assay against human melanoma A375 and colon adenocarcinoma HT-29 cell lines. In general, the synthesized compounds were more cytotoxic against HT-29 than A375. 3-((4-Methoxyphenyl)(3-oxo-3-(2-(2-oxoindolin-3-ylidene)hydrazinyl)propyl)amino)-N′-(2-oxoindolin-3-ylidene)propanehydrazide and (N′,N‴)-1,1′-(methylenebis(4,1-phenylene))bis(5-oxo-N′-(2-oxoindolin-3-ylidene)pyrrolidine-3-carbohydrazide) were identified as the most active compounds against HT-29 in 2D and 3D cell cultures. The same compounds showed the highest antioxidant activity among the synthesized compounds screened by ferric reducing antioxidant power assay (FRAP). Their antioxidant activity is on par with that of a well-known antioxidant ascorbic acid. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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9 pages, 1548 KiB

Open AccessCommunication

FTY720 Inhibits Expansion of Breast Cancer Stem Cells via PP2A Activation

by Naoya Hirata, Shigeru Yamada, Shota Yanagida, Atsushi Ono and Yasunari Kanda

Int. J. Mol. Sci. 2021, 22(14), 7259; https://doi.org/10.3390/ijms22147259 - 6 Jul 2021

Cited by 12 | Viewed by 2770

Abstract

Growing evidence suggests that breast cancer originates from a minor population of cancer cells termed cancer stem cells (CSCs), which can be identified by aldehyde dehydrogenase (ALDH) activity-based flow cytometry analysis. However, novel therapeutic drugs for the eradication of CSCs have not been [...] Read more.

Growing evidence suggests that breast cancer originates from a minor population of cancer cells termed cancer stem cells (CSCs), which can be identified by aldehyde dehydrogenase (ALDH) activity-based flow cytometry analysis. However, novel therapeutic drugs for the eradication of CSCs have not been discovered yet. Recently, drug repositioning, which finds new medical uses from existing drugs, has been expected to facilitate drug discovery. We have previously reported that sphingosine kinase 1 (SphK1) induced proliferation of breast CSCs. In the present study, we focused on the immunosuppressive agent FTY720 (also known as fingolimod or Gilenya), since FTY720 is known to be an inhibitor of SphK1. We found that FTY720 blocked both proliferation of ALDH-positive cells and formation of mammospheres. In addition, we showed that FTY720 reduced the expression of stem cell markers such as Oct3/4, Sox2 and Nanog via upregulation of protein phosphatase 2A (PP2A). These results suggest that FTY720 is an effective drug for breast CSCs in vitro. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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18 pages, 4444 KiB

Open AccessArticle

Dextran-Curcumin Nanosystems Inhibit Cell Growth and Migration Regulating the Epithelial to Mesenchymal Transition in Prostate Cancer Cells

by Emilia Bevacqua, Manuela Curcio, Federica Saletta, Orazio Vittorio, Giuseppe Cirillo and Paola Tucci

Int. J. Mol. Sci. 2021, 22(13), 7013; https://doi.org/10.3390/ijms22137013 - 29 Jun 2021

Cited by 15 | Viewed by 2641

Abstract

Functional nanocarriers which are able to simultaneously vectorize drugs to the site of interest and exert their own cytotoxic activity represent a significant breakthrough in the search for effective anticancer strategies with fewer side effects than conventional chemotherapeutics. Here, we propose previously developed, [...] Read more.

Functional nanocarriers which are able to simultaneously vectorize drugs to the site of interest and exert their own cytotoxic activity represent a significant breakthrough in the search for effective anticancer strategies with fewer side effects than conventional chemotherapeutics. Here, we propose previously developed, self-assembling dextran-curcumin nanoparticles for the treatment of prostate cancer in combination therapy with Doxorubicin (DOXO). Biological effectiveness was investigated by evaluating the cell viability in either cancer and normal cells, reactive oxygen species (ROS) production, apoptotic effect, interference with the cell cycle, and the ability to inhibit cell migration and reverse the epithelial to mesenchymal transition (EMT). The results proved a significant enhancement of curcumin efficiency upon immobilization in nanoparticles: IC₅₀ reduced by a half, induction of apoptotic effect, and improved ROS production (from 67 to 134%) at low concentrations. Nanoparticles guaranteed a pH-dependent DOXO release, with a more efficient release in acidic environments. Finally, a synergistic effect between nanoparticles and Doxorubicin was demonstrated, with the free curcumin showing additive activity. Although in vivo studies are required to support the findings of this study, these preliminary in vitro data can be considered a proof of principle for the design of an effective therapy for prostate cancer treatment. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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22 pages, 60745 KiB

Open AccessArticle

Plumbagin, a Natural Product with Potent Anticancer Activities, Binds to and Inhibits Dihydroorotase, a Key Enzyme in Pyrimidine Biosynthesis

by Hong-Hsiang Guan, Yen-Hua Huang, En-Shyh Lin, Chun-Jung Chen and Cheng-Yang Huang

Int. J. Mol. Sci. 2021, 22(13), 6861; https://doi.org/10.3390/ijms22136861 - 25 Jun 2021

Cited by 27 | Viewed by 3531

Abstract

Dihydroorotase (DHOase) is the third enzyme in the de novo biosynthesis pathway for pyrimidine nucleotides, and an attractive target for potential anticancer chemotherapy. By screening plant extracts and performing GC–MS analysis, we identified and characterized that the potent anticancer drug plumbagin (PLU), isolated [...] Read more.

Dihydroorotase (DHOase) is the third enzyme in the de novo biosynthesis pathway for pyrimidine nucleotides, and an attractive target for potential anticancer chemotherapy. By screening plant extracts and performing GC–MS analysis, we identified and characterized that the potent anticancer drug plumbagin (PLU), isolated from the carnivorous plant Nepenthes miranda, was a competitive inhibitor of DHOase. We also solved the complexed crystal structure of yeast DHOase with PLU (PDB entry 7CA1), to determine the binding interactions and investigate the binding modes. Mutational and structural analyses indicated the binding of PLU to DHOase through loop-in mode, and this dynamic loop may serve as a drug target. PLU exhibited cytotoxicity on the survival, migration, and proliferation of 4T1 cells and induced apoptosis. These results provide structural insights that may facilitate the development of new inhibitors targeting DHOase, for further clinical anticancer chemotherapies. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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19 pages, 6830 KiB

Open AccessArticle

Antitumor Activity of Nitazoxanide against Colon Cancers: Molecular Docking and Experimental Studies Based on Wnt/β-Catenin Signaling Inhibition

by Noha M. Abd El-Fadeal, Mohamed S. Nafie, Mohammed K. El-kherbetawy, Amr El-mistekawy, Hala M. F. Mohammad, Alaaeldeen M. Elbahaie, Abdullah A. Hashish, Suliman Y. Alomar, Sheka Yagub Aloyouni, Mohamed El-dosoky, Khaled M. Morsy and Sawsan A. Zaitone

Int. J. Mol. Sci. 2021, 22(10), 5213; https://doi.org/10.3390/ijms22105213 - 14 May 2021

Cited by 14 | Viewed by 4548

Abstract

In colon cancer, wingless (Wnt)/β-catenin signaling is frequently upregulated; however, the creation of a molecular therapeutic agent targeting this pathway is still under investigation. This research aimed to study how nitazoxanide can affect Wnt/β-catenin signaling in colon cancer cells (HCT-116) and a mouse [...] Read more.

In colon cancer, wingless (Wnt)/β-catenin signaling is frequently upregulated; however, the creation of a molecular therapeutic agent targeting this pathway is still under investigation. This research aimed to study how nitazoxanide can affect Wnt/β-catenin signaling in colon cancer cells (HCT-116) and a mouse colon cancer model. Our study included 2 experiments; the first was to test the cytotoxic activity of nitazoxanide in an in vitro study on a colon cancer cell line (HCT-116) versus normal colon cells (FHC) and to highlight the proapoptotic effect by MTT assay, flow cytometry and real-time polymerase chain reaction (RT-PCR). The second experiment tested the in vivo cytotoxic effect of nitazoxanide against 1,2-dimethylhydrazine (DMH) prompted cancer in mice. Mice were grouped as saline, DMH control and DMH + nitazoxanide [100 or 200 mg per kg]. Colon levels of Wnt and β-catenin proteins were assessed by Western blotting while proliferation was measured via immunostaining for proliferating cell nuclear antigen (PCNA). Treating HCT-116 cells with nitazoxanide (inhibitory concentration 50 (IC50) = 11.07 µM) revealed that it has a more cytotoxic effect when compared to 5-flurouracil (IC50 = 11.36 µM). Moreover, it showed relatively high IC50 value (non-cytotoxic) against the normal colon cells. Nitazoxanide induced apoptosis by 15.86-fold compared to control and arrested the cell cycle. Furthermore, nitazoxanide upregulated proapoptotic proteins (P53 and BAX) and caspases but downregulated BCL-2. Nitazoxanide downregulated Wnt/β-catenin/glycogen synthase kinase-3β (GSK-3β) signaling and PCNA staining in the current mouse model. Hence, our findings highlighted the cytotoxic effect of nitazoxanide and pointed out the effect on Wnt/β-catenin/GSK-3β signaling. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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12 pages, 588 KiB

Open AccessCommunication

Novel Symmetrical Cage Compounds as Inhibitors of the Symmetrical MRP4-Efflux Pump for Anticancer Therapy

by David Kreutzer, Henry Döring, Peter Werner, Christoph A. Ritter and Andreas Hilgeroth

Int. J. Mol. Sci. 2021, 22(10), 5098; https://doi.org/10.3390/ijms22105098 - 12 May 2021

Cited by 2 | Viewed by 1872

Abstract

Within the last decades cancer treatment improved by the availability of more specifically acting drugs that address molecular target structures in cancer cells. However, those target-sensitive drugs suffer from ongoing resistances resulting from mutations and moreover they are affected by the cancer phenomenon [...] Read more.

Within the last decades cancer treatment improved by the availability of more specifically acting drugs that address molecular target structures in cancer cells. However, those target-sensitive drugs suffer from ongoing resistances resulting from mutations and moreover they are affected by the cancer phenomenon of multidrug resistance. A multidrug resistant cancer can hardly be treated with the common drugs, so that there have been long efforts to develop drugs to combat that resistance. Transmembrane efflux pumps are the main cause of the multidrug resistance in cancer. Early inhibitors disappointed in cancer treatment without a proof of expression of a respective efflux pump. Recent studies in efflux pump expressing cancer show convincing effects of those inhibitors. Based on the molecular symmetry of the efflux pump multidrug resistant protein (MRP) 4 we synthesized symmetric inhibitors with varied substitution patterns. They were evaluated in a MRP4-overexpressing cancer cell line model to prove structure-dependent effects on the inhibition of the efflux pump activity in an uptake assay of a fluorescent MRP4 substrate. The most active compound was tested to resentisize the MRP4-overexpressing cell line towards a clinically relevant anticancer drug as proof-of-principle to encourage for further preclinical studies. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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25 pages, 9520 KiB

Open AccessArticle

The Anti-Cancer Effects of a Zotarolimus and 5-Fluorouracil Combination Treatment on A549 Cell-Derived Tumors in BALB/c Nude Mice

by Ching-Feng Wu, Ching-Yang Wu, Robin Y.-Y. Chiou, Wei-Cheng Yang, Chuen-Fu Lin, Chao-Min Wang, Po-Hsun Hou, Tzu-Chun Lin, Chan-Yen Kuo and Geng-Ruei Chang

Int. J. Mol. Sci. 2021, 22(9), 4562; https://doi.org/10.3390/ijms22094562 - 27 Apr 2021

Cited by 9 | Viewed by 4525

Abstract

Zotarolimus is a semi-synthetic derivative of rapamycin and a novel immunosuppressive agent used to prevent graft rejection. The pharmacological pathway of zotarolimus restricts the kinase activity of the mammalian target of rapamycin (mTOR), which potentially leads to reductions in cell division, cell growth, [...] Read more.

Zotarolimus is a semi-synthetic derivative of rapamycin and a novel immunosuppressive agent used to prevent graft rejection. The pharmacological pathway of zotarolimus restricts the kinase activity of the mammalian target of rapamycin (mTOR), which potentially leads to reductions in cell division, cell growth, cell proliferation, and inflammation. These pathways have a critical influence on tumorigenesis. This study aims to examine the anti-tumor effect of zotarolimus or zotarolimus combined with 5-fluorouracil (5-FU) on A549 human lung adenocarcinoma cell line implanted in BALB/c nude mice by estimating tumor growth, apoptosis expression, inflammation, and metastasis. We established A549 xenografts in nude mice, following which we randomly divided the mice into four groups: control, 5-FU (100 mg/kg/week), zotarolimus (2 mg/kg/day), and zotarolimus combined with 5-FU. Compared the results with those for control mice, we found that mice treated with zotarolimus or zotarolimus combined with 5-FU retarded tumor growth; increased tumor apoptosis through the enhanced expression of cleaved caspase 3 and extracellular signal-regulated kinase (ERK) phosphorylation; decreased inflammation cytokines levels (e.g., IL-1β, TNF-α, and IL-6); reduced inflammation-related factors such as cyclooxygenase-2 (COX-2) protein and nuclear factor-κB (NF-κB) mRNA; enhanced anti-inflammation-related factors including IL-10 and inhibitor of NF-κB kinase α (IκBα) mRNA; and inhibited metastasis-related factors such as transforming growth factor β (TGF-β), CD44, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF). Notably, mice treated with zotarolimus combined with 5-FU had significantly retarded tumor growth, reduced tumor size, and increased tumor inhibition compared with the groups of mice treated with 5-FU or zotarolimus alone. The in vivo study confirmed that zotarolimus or zotarolimus combined with 5-FU could retard lung adenocarcinoma growth and inhibit tumorigenesis. Zotarolimus and 5-FU were found to have an obvious synergistic tumor-inhibiting effect on lung adenocarcinoma. Therefore, both zotarolimus alone and zotarolimus combined with 5-FU may be potential anti-tumor agents for treatment of human lung adenocarcinoma. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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16 pages, 4470 KiB

Open AccessArticle

Proliferation to Apoptosis Tumor Cell Ratio as a Biomarker to Improve Clinical Management of Pre-Malignant and Symptomatic Plasma Cell Neoplasms

by María A. Vasco-Mogorrón, José A. Campillo, Adela Periago, Valentin Cabañas, Mercedes Berenguer, María C. García-Garay, Lourdes Gimeno, María F. Soto-Ramírez, María D. Martínez-Hernández, Manuel Muro and Alfredo Minguela

Int. J. Mol. Sci. 2021, 22(8), 3895; https://doi.org/10.3390/ijms22083895 - 9 Apr 2021

Cited by 3 | Viewed by 2756

Abstract

Proliferation and apoptosis of neoplastic cells are prognostic biomarkers in plasma cell neoplasms (PCNs). The prognostic capacity of proliferation to apoptosis ratio (Ratio-PA) in the era of immunomodulatory treatments is re-evaluated in 316 gammopathy of undetermined significance (MGUS), 57 smoldering multiple myeloma (SMM), [...] Read more.

Proliferation and apoptosis of neoplastic cells are prognostic biomarkers in plasma cell neoplasms (PCNs). The prognostic capacity of proliferation to apoptosis ratio (Ratio-PA) in the era of immunomodulatory treatments is re-evaluated in 316 gammopathy of undetermined significance (MGUS), 57 smoldering multiple myeloma (SMM), and 266 multiple myeloma (MM) patients. Ratio-PA of 0.77 ± 0.12, 1.94 ± 0.52, and 11.2 ± 0.7 (p < 0.0001) were observed in MGUS, SMM, and MM patients. Ten-year overall survival (10y-OS) rates for patients with low/high Ratio-PA were 93.5%/77.3% p < 0.0001) for MGUS, 82.5%/64.7% (p < 0.05) for SMM, and 62.3%/47.0% (p < 0.05) for MM. For patients with low, intermediate, and high risk, 10y-OS for low/high Ratio-PA were 95.5%/72.9% (p < 0.0001), 74.2%/50.4% (p < 0.0001), and 35.3%/20.0% (p = 0.836), respectively. Ratio-PA was an independent prognostic factor for OS (HR = 2.119, p < 0.0001, Harrell-C-statistic = 0.7440 ± 0.0194) when co-analyzed with sex, age, and standard risk. In patients with Ratio-PA^high, only first-line therapy with VRd/VTd, but not PAD/VCD, coupled with ASCT was associated with high 10y-OS (82.7%). Tumor cell Ratio-PA estimated at diagnosis offers a prognostic biomarker that complements standard risk stratification and helps to guide the clinical management of pre-malignant and symptomatic PCNs. Every effort should be made to provide first-line therapies including VTd or VRd associated with ASCT to patients with Ratio-PA^high at higher risk of progression and death. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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20 pages, 4622 KiB

Open AccessArticle

Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-Hydrazones

by Mabrouk Horchani, Gerardo Della Sala, Alessia Caso, Federica D’Aria, Germana Esposito, Ilaria Laurenzana, Concetta Giancola, Valeria Costantino, Hichem Ben Jannet and Anis Romdhane

Int. J. Mol. Sci. 2021, 22(5), 2742; https://doi.org/10.3390/ijms22052742 - 8 Mar 2021

Cited by 17 | Viewed by 3198

Abstract

Chemotherapy represents the most applied approach to cancer treatment. Owing to the frequent onset of chemoresistance and tumor relapses, there is an urgent need to discover novel and more effective anticancer drugs. In the search for therapeutic alternatives to treat the cancer disease, [...] Read more.

Chemotherapy represents the most applied approach to cancer treatment. Owing to the frequent onset of chemoresistance and tumor relapses, there is an urgent need to discover novel and more effective anticancer drugs. In the search for therapeutic alternatives to treat the cancer disease, a series of hybrid pyrazolo[3,4-d]pyrimidin-4(5H)-ones tethered with hydrazide-hydrazones, 5a–h, was synthesized from condensation reaction of pyrazolopyrimidinone-hydrazide 4 with a series of arylaldehydes in ethanol, in acid catalysis. In vitro assessment of antiproliferative effects against MCF-7 breast cancer cells, unveiled that 5a, 5e, 5g, and 5h were the most effective compounds of the series and exerted their cytotoxic activity through apoptosis induction and G0/G1 phase cell-cycle arrest. To explore their mechanism at a molecular level, 5a, 5e, 5g, and 5h were evaluated for their binding interactions with two well-known anticancer targets, namely the epidermal growth factor receptor (EGFR) and the G-quadruplex DNA structures. Molecular docking simulations highlighted high binding affinity of 5a, 5e, 5g, and 5h towards EGFR. Circular dichroism (CD) experiments suggested 5a as a stabilizer agent of the G-quadruplex from the Kirsten ras (KRAS) oncogene promoter. In the light of these findings, we propose the pyrazolo-pyrimidinone scaffold bearing a hydrazide-hydrazone moiety as a lead skeleton for designing novel anticancer compounds. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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18 pages, 2150 KiB

Open AccessArticle

Design and Synthesis of Novel Imidazole Derivatives Possessing Triazole Pharmacophore with Potent Anticancer Activity, and In Silico ADMET with GSK-3β Molecular Docking Investigations

by Fawzia Al-blewi, Salma Akram Shaikh, Arshi Naqvi, Faizah Aljohani, Mohamed Reda Aouad, Saleh Ihmaid and Nadjet Rezki

Int. J. Mol. Sci. 2021, 22(3), 1162; https://doi.org/10.3390/ijms22031162 - 25 Jan 2021

Cited by 29 | Viewed by 4446

Abstract

A library of novel imidazole-1,2,3-triazole hybrids were designed and synthesized based on the hybrid pharmacophore approach. Therefore, copper(I)catalyzed click reaction of thiopropargylated-imidazole 2 with several organoazides yielded two sets of imidazole-1,2,3-triazole hybrids carrying different un/functionalized alkyl/aryl side chains 4a–k and 6a [...] Read more.

A library of novel imidazole-1,2,3-triazole hybrids were designed and synthesized based on the hybrid pharmacophore approach. Therefore, copper(I)catalyzed click reaction of thiopropargylated-imidazole 2 with several organoazides yielded two sets of imidazole-1,2,3-triazole hybrids carrying different un/functionalized alkyl/aryl side chains 4a–k and 6a–e. After full spectroscopic characterization using different spectral techniques (IR, ¹H, ¹³C NMR) and elemental analyses, the resulted adducts were screened for their anticancer activity against four cancer cell lines (Caco-2, HCT-116, HeLa, and MCF-7) by the MTT assay and showed significant activity. In-silico molecular docking study was also investigated on one of the prominent cancer target receptors, i.e., glycogen synthase kinase-3β (GSK-3β), revealing a good binding interaction with our potent compound, 4k and was in agreement with the in vitro cytotoxic results. In addition, the ADMET profile was assessed for these novel derivatives to get an insight on their pharmacokinetic/dynamic attributes. Finally, this research design and synthesis offered click chemistry products with interesting biological motifs mainly 1,2,3 triazoles linked to phenyl imidazole as promising candidates for further investigation as anticancer drugs. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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16 pages, 3379 KiB

Open AccessArticle

Synergistic Anticancer Activity of N-Hydroxy-7-(2-Naphthylthio) Heptanomide, Sorafenib, and Radiation Therapy in Patient-Derived Anaplastic Thyroid Cancer Models

by Hyeok Jun Yun, Hee Jun Kim, Jungmin Kim, Sang Yong Kim, Hang-Seok Chang, Cheong Soo Park, Ho-Jin Chang and Ki Cheong Park

Int. J. Mol. Sci. 2021, 22(2), 536; https://doi.org/10.3390/ijms22020536 - 7 Jan 2021

Cited by 7 | Viewed by 2408

Abstract

Anaplastic thyroid cancer (ATC) is an undifferentiated and advanced form of thyroid cancer, accompanied with a high ratio of epigenetic adjustment, which occurs more than genetic mutations. In this study, we aimed to evaluate the synergistic anticancer effect (in vitro and in vivo) [...] Read more.

Anaplastic thyroid cancer (ATC) is an undifferentiated and advanced form of thyroid cancer, accompanied with a high ratio of epigenetic adjustment, which occurs more than genetic mutations. In this study, we aimed to evaluate the synergistic anticancer effect (in vitro and in vivo) of the new combination of N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA) and sorafenib with radiation therapy in pre-clinical models of ATC. The ATC cell lines, YUMC-A1 and YUMC-A2, were isolated from the current patients who were treated with HNHA and sorafenib, either as monotherapy or combination therapy. Synergistic anticancer effect of the combination therapy on the intracellular signaling pathways and cell cycle was assessed via flow cytometry and immunoblot analysis. To examine tumor shrinkage activity in vivo, an ATC cell line-derived mouse xenograft model was used. Results showed that the combination therapy of HNHA and sorafenib with radiation promoted tumor suppression via caspase cleavage and cell cycle arrest in patient-derived ATC. In addition, the combination therapy of HNHA and sorafenib with radiation was more effective against ATC than therapy with HNHA or sorafenib with radiation. Thus, the combination of HNHA and sorafenib with radiation may be used as a novel curative approach for the treatment of ATC. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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Review

Jump to: Research

16 pages, 610 KiB

Open AccessReview

A Hot Topic: Cancer Immunotherapy and Natural Killer Cells

by Tatiana Michel, Markus Ollert and Jacques Zimmer

Int. J. Mol. Sci. 2022, 23(2), 797; https://doi.org/10.3390/ijms23020797 - 12 Jan 2022

Cited by 10 | Viewed by 4418

Abstract

Despite significant progress in recent years, the therapeutic approach of the multiple different forms of human cancer often remains a challenge. Besides the well-established cancer surgery, radiotherapy and chemotherapy, immunotherapeutic strategies gain more and more attention, and some of them have already been [...] Read more.

Despite significant progress in recent years, the therapeutic approach of the multiple different forms of human cancer often remains a challenge. Besides the well-established cancer surgery, radiotherapy and chemotherapy, immunotherapeutic strategies gain more and more attention, and some of them have already been successfully introduced into the clinic. Among these, immunotherapy based on natural killer (NK) cells is considered as one of the most promising options. In the present review, we will expose the different possibilities NK cells offer in this context, compare data about the theoretical background and mechanism(s) of action, report some results of clinical trials and identify several very recent trends. The pharmaceutical industry is quite interested in NK cell immunotherapy, which will benefit the speed of progress in the field. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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22 pages, 5887 KiB

Open AccessReview

Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?

by Raj Kumar Mongre, Chandra Bhushan Mishra, Arvind Kumar Shukla, Amresh Prakash, Samil Jung, Md Ashraf-Uz-Zaman and Myeong-Sok Lee

Int. J. Mol. Sci. 2021, 22(21), 11659; https://doi.org/10.3390/ijms222111659 - 28 Oct 2021

Cited by 24 | Viewed by 4960

Abstract

GLOBOCAN 2020 estimated more than 19.3 million new cases, and about 10 million patients were deceased from cancer in 2020. Clinical manifestations showed that several growth factor receptors consisting of transmembrane and cytoplasmic tyrosine kinase (TK) domains play a vital role in cancer [...] Read more.

GLOBOCAN 2020 estimated more than 19.3 million new cases, and about 10 million patients were deceased from cancer in 2020. Clinical manifestations showed that several growth factor receptors consisting of transmembrane and cytoplasmic tyrosine kinase (TK) domains play a vital role in cancer progression. Receptor tyrosine kinases (RTKs) are crucial intermediaries of the several cellular pathways and carcinogenesis that directly affect the prognosis and survival of higher tumor grade patients. Tyrosine kinase inhibitors (TKIs) are efficacious drugs for targeted therapy of various cancers. Therefore, RTKs have become a promising therapeutic target to cure cancer. A recent report shows that TKIs are vital mediators of signal transduction and cancer cell proliferation, angiogenesis, and apoptosis. In this review, we discuss the structure and function of RTKs to explore their prime role in cancer therapy. Various TKIs have been developed to date that contribute a lot to treating several types of cancer. These TKI based anticancer drug molecules are also discussed in detail, incorporating their therapeutic efficacy, mechanism of action, and side effects. Additionally, this article focuses on TKIs which are running in the clinical trial and pre-clinical studies. Further, to gain insight into the pathophysiological mechanism of TKIs, we also reviewed the impact of RTK resistance on TKI clinical drugs along with their mechanistic acquired resistance in different cancer types. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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16 pages, 1497 KiB

Open AccessReview

Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives

by Svetlana N. Aleksakhina and Evgeny N. Imyanitov

Int. J. Mol. Sci. 2021, 22(20), 10931; https://doi.org/10.3390/ijms222010931 - 10 Oct 2021

Cited by 25 | Viewed by 6040

Abstract

The administration of many cancer drugs is tailored to genetic tests. Some genomic events, e.g., alterations of EGFR or BRAF oncogenes, result in the conformational change of the corresponding proteins and call for the use of mutation-specific compounds. Other genetic perturbations, e.g., HER2 [...] Read more.

The administration of many cancer drugs is tailored to genetic tests. Some genomic events, e.g., alterations of EGFR or BRAF oncogenes, result in the conformational change of the corresponding proteins and call for the use of mutation-specific compounds. Other genetic perturbations, e.g., HER2 amplifications, ALK translocations or MET exon 14 skipping mutations, cause overproduction of the entire protein or its kinase domain. There are multilocus assays that provide integrative characteristics of the tumor genome, such as the analysis of tumor mutation burden or deficiency of DNA repair. Treatment planning for non-small cell lung cancer requires testing for EGFR, ALK, ROS1, BRAF, MET, RET and KRAS gene alterations. Colorectal cancer patients need to undergo KRAS, NRAS, BRAF, HER2 and microsatellite instability analysis. The genomic examination of breast cancer includes testing for HER2 amplification and PIK3CA activation. Melanomas are currently subjected to BRAF and, in some instances, KIT genetic analysis. Predictive DNA assays have also been developed for thyroid cancers, cholangiocarcinomas and urinary bladder tumors. There is an increasing utilization of agnostic testing which involves the analysis of all potentially actionable genes across all tumor types. The invention of genomically tailored treatment has resulted in a spectacular improvement in disease outcomes for a significant portion of cancer patients. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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15 pages, 2864 KiB

Open AccessReview

Photodynamic Therapy Induced Cell Death Mechanisms in Breast Cancer

by Dimakatso R. Mokoena, Blassan P. George and Heidi Abrahamse

Int. J. Mol. Sci. 2021, 22(19), 10506; https://doi.org/10.3390/ijms221910506 - 29 Sep 2021

Cited by 34 | Viewed by 3879

Abstract

Breast cancer is the second most common cancer globally and the pioneering cause of mortality among women. It usually begins from the ducts or lobules, referred to as ductal carcinoma in situ, or lobular carcinoma in situ. Age, mutations in Breast Cancer Gene [...] Read more.

Breast cancer is the second most common cancer globally and the pioneering cause of mortality among women. It usually begins from the ducts or lobules, referred to as ductal carcinoma in situ, or lobular carcinoma in situ. Age, mutations in Breast Cancer Gene 1 or 2 (BRCA1 or BRCA2) genes, and dense breast tissue are the highest risk factors. Current treatments are associated with various side effects, relapse, and a low quality of life. Although conventional treatments, such as surgery and chemotherapy, have been used for decades, their adverse side effects on normal cells and tissues pose a major weakness, which calls for a non-invasive treatment option. Photodynamic therapy (PDT) has proven to be a promising form of cancer therapy. It is less invasive, target-specific, and with reduced cytotoxicity to normal cells and tissues. It involves the use of a photosensitizer (PS) and light at a specific wavelength to produce reactive oxygen species. One of the reasons for the target specificity is associated with the dense vascularization of cancer tissues, which tends to increase the surface area for the PS uptake. Photosensitizers are light-sensitive molecules, which result in cancer cell destruction followed by light irradiation. Depending on the localization of the PS within the cancer cell, its destruction may be via apoptosis, necrosis, or autophagy. This review focuses on the breast cancer etiopathology and PDT-induced cell death mechanisms in breast cancer cells. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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25 pages, 2918 KiB

Open AccessReview

BH3 Mimetics in Hematologic Malignancies

by Pavel Klener, Dana Sovilj, Nicol Renesova and Ladislav Andera

Int. J. Mol. Sci. 2021, 22(18), 10157; https://doi.org/10.3390/ijms221810157 - 21 Sep 2021

Cited by 14 | Viewed by 5162

Abstract

Hematologic malignancies (HM) comprise diverse cancers of lymphoid and myeloid origin, including lymphomas (approx. 40%), chronic lymphocytic leukemia (CLL, approx. 15%), multiple myeloma (MM, approx. 15%), acute myeloid leukemia (AML, approx. 10%), and many other diseases. Despite considerable improvement in treatment options and [...] Read more.

Hematologic malignancies (HM) comprise diverse cancers of lymphoid and myeloid origin, including lymphomas (approx. 40%), chronic lymphocytic leukemia (CLL, approx. 15%), multiple myeloma (MM, approx. 15%), acute myeloid leukemia (AML, approx. 10%), and many other diseases. Despite considerable improvement in treatment options and survival parameters in the new millennium, many patients with HM still develop chemotherapy‑refractory diseases and require re-treatment. Because frontline therapies for the majority of HM (except for CLL) are still largely based on classical cytostatics, the relapses are often associated with defects in DNA damage response (DDR) pathways and anti-apoptotic blocks exemplified, respectively, by mutations or deletion of the TP53 tumor suppressor, and overexpression of anti-apoptotic proteins of the B-cell lymphoma 2 (BCL2) family. BCL2 homology 3 (BH3) mimetics represent a novel class of pro-apoptotic anti-cancer agents with a unique mode of action—direct targeting of mitochondria independently of TP53 gene aberrations. Consequently, BH3 mimetics can effectively eliminate even non-dividing malignant cells with adverse molecular cytogenetic alterations. Venetoclax, the nanomolar inhibitor of BCL2 anti-apoptotic protein has been approved for the therapy of CLL and AML. Numerous venetoclax-based combinatorial treatment regimens, next-generation BCL2 inhibitors, and myeloid cell leukemia 1 (MCL1) protein inhibitors, which are another class of BH3 mimetics with promising preclinical results, are currently being tested in several clinical trials in patients with diverse HM. These pivotal trials will soon answer critical questions and concerns about these innovative agents regarding not only their anti-tumor efficacy but also potential side effects, recommended dosages, and the optimal length of therapy as well as identification of reliable biomarkers of sensitivity or resistance. Effective harnessing of the full therapeutic potential of BH3 mimetics is a critical mission as it may directly translate into better management of the aggressive forms of HM and could lead to significantly improved survival parameters and quality of life in patients with urgent medical needs. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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19 pages, 1646 KiB

Open AccessReview

Step-by-Step Immune Activation for Suicide Gene Therapy Reinforcement

by Irina Alekseenko, Alexey Kuzmich, Liya Kondratyeva, Sofia Kondratieva, Victor Pleshkan and Eugene Sverdlov

Int. J. Mol. Sci. 2021, 22(17), 9376; https://doi.org/10.3390/ijms22179376 - 29 Aug 2021

Cited by 6 | Viewed by 4451

Abstract

Gene-directed enzyme prodrug gene therapy (GDEPT) theoretically represents a useful method to carry out chemotherapy for cancer with minimal side effects through the formation of a chemotherapeutic agent inside cancer cells. However, despite great efforts, promising preliminary results, and a long period of [...] Read more.

Gene-directed enzyme prodrug gene therapy (GDEPT) theoretically represents a useful method to carry out chemotherapy for cancer with minimal side effects through the formation of a chemotherapeutic agent inside cancer cells. However, despite great efforts, promising preliminary results, and a long period of time (over 25 years) since the first mention of this method, GDEPT has not yet reached the clinic. There is a growing consensus that optimal cancer therapies should generate robust tumor-specific immune responses. The advent of checkpoint immunotherapy has yielded new highly promising avenues of study in cancer therapy. For such therapy, it seems reasonable to use combinations of different immunomodulators alongside traditional methods, such as chemotherapy and radiotherapy, as well as GDEPT. In this review, we focused on non-viral gene immunotherapy systems combining the intratumoral production of toxins diffused by GDEPT and immunomodulatory molecules. Special attention was paid to the applications and mechanisms of action of the granulocyte-macrophage colony-stimulating factor (GM–CSF), a cytokine that is widely used but shows contradictory effects. Another method to enhance the formation of stable immune responses in a tumor, the use of danger signals, is also discussed. The process of dying from GDEPT cancer cells initiates danger signaling by releasing damage-associated molecular patterns (DAMPs) that exert immature dendritic cells by increasing antigen uptake, maturation, and antigen presentation to cytotoxic T-lymphocytes. We hypothesized that the combined action of this danger signal and GM–CSF issued from the same dying cancer cell within a limited space would focus on a limited pool of immature dendritic cells, thus acting synergistically and enhancing their maturation and cytotoxic T-lymphocyte attraction potential. We also discuss the problem of enhancing the cancer specificity of the combined GDEPT–GM–CSF–danger signal system by means of artificial cancer specific promoters or a modified delivery system. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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10 pages, 1802 KiB

Open AccessReview

GPCR Partners as Cancer Driver Genes: Association with PH-Signal Proteins in a Distinctive Signaling Network

by Jeetendra Kumar Nag, Hodaya Malka, Priyanga Appasamy, Shoshana Sedley and Rachel Bar-Shavit

Int. J. Mol. Sci. 2021, 22(16), 8985; https://doi.org/10.3390/ijms22168985 - 20 Aug 2021

Cited by 1 | Viewed by 2291

Abstract

The essential role of G-protein coupled receptors (GPCRs) in tumor growth is recognized, yet a GPCR based drug in cancer is rare. Understanding the molecular path of a tumor driver gene may lead to the design and development of an effective drug. For [...] Read more.

The essential role of G-protein coupled receptors (GPCRs) in tumor growth is recognized, yet a GPCR based drug in cancer is rare. Understanding the molecular path of a tumor driver gene may lead to the design and development of an effective drug. For example, in members of protease-activated receptor (PAR) family (e.g., PAR₁ and PAR₂), a novel PH-binding motif is allocated as critical for tumor growth. Animal models have indicated the generation of large tumors in the presence of PAR₁ or PAR₂ oncogenes. These tumors showed effective inhibition when the PH-binding motif was either modified or were inhibited by a specific inhibitor targeted to the PH-binding motif. In the second part of the review we discuss several aspects of some cardinal GPCRs in tumor angiogenesis. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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17 pages, 1603 KiB

Open AccessReview

TNFα and Immune Checkpoint Inhibition: Friend or Foe for Lung Cancer?

by Thomas Benoot, Elisa Piccioni, Kirsten De Ridder and Cleo Goyvaerts

Int. J. Mol. Sci. 2021, 22(16), 8691; https://doi.org/10.3390/ijms22168691 - 13 Aug 2021

Cited by 24 | Viewed by 4847

Abstract

Tumor necrosis factor-alpha (TNFα) can bind two distinct receptors (TNFR1/2). The transmembrane form (tmTNFα) preferentially binds to TNFR2. Upon tmTNFα cleavage by the TNF-alpha-converting enzyme (TACE), its soluble (sTNFα) form is released with higher affinity for TNFR1. This assortment empowers TNFα with a [...] Read more.

Tumor necrosis factor-alpha (TNFα) can bind two distinct receptors (TNFR1/2). The transmembrane form (tmTNFα) preferentially binds to TNFR2. Upon tmTNFα cleavage by the TNF-alpha-converting enzyme (TACE), its soluble (sTNFα) form is released with higher affinity for TNFR1. This assortment empowers TNFα with a plethora of opposing roles in the processes of tumor cell survival (and apoptosis) and anti-tumor immune stimulation (and suppression), in addition to angiogenesis and metastases. Its functions and biomarker potential to predict cancer progression and response to immunotherapy are reviewed here, with a focus on lung cancer. By mining existing sequencing data, we further demonstrate that the expression levels of TNF and TACE are significantly decreased in lung adenocarcinoma patients, while the TNFR1/TNFR2 balance are increased. We conclude that the biomarker potential of TNFα alone will most likely not provide conclusive findings, but that TACE could have a key role along with the delicate balance of sTNFα/tmTNFα as well as TNFR1/TNFR2, hence stressing the importance of more research into the potential of rationalized treatments that combine TNFα pathway modulators with immunotherapy for lung cancer patients. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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23 pages, 1641 KiB

Open AccessReview

The Updating of Biological Functions of Methyltransferase SETDB1 and Its Relevance in Lung Cancer and Mesothelioma

by Li Yuan, Boshu Sun, Liangliang Xu, Limin Chen and Wenbin Ou

Int. J. Mol. Sci. 2021, 22(14), 7416; https://doi.org/10.3390/ijms22147416 - 10 Jul 2021

Cited by 7 | Viewed by 4951

Abstract

SET domain bifurcated 1 (SETDB1) is a histone H3 lysine 9 (H3K9) methyltransferase that exerts important effects on epigenetic gene regulation. SETDB1 complexes (SETDB1-KRAB-KAP1, SETDB1-DNMT3A, SETDB1-PML, SETDB1-ATF7IP-MBD1) play crucial roles in the processes of histone methylation, transcriptional suppression and chromatin remodelling. Therefore, aberrant [...] Read more.

SET domain bifurcated 1 (SETDB1) is a histone H3 lysine 9 (H3K9) methyltransferase that exerts important effects on epigenetic gene regulation. SETDB1 complexes (SETDB1-KRAB-KAP1, SETDB1-DNMT3A, SETDB1-PML, SETDB1-ATF7IP-MBD1) play crucial roles in the processes of histone methylation, transcriptional suppression and chromatin remodelling. Therefore, aberrant trimethylation at H3K9 due to amplification, mutation or deletion of SETDB1 may lead to transcriptional repression of various tumour-suppressing genes and other related genes in cancer cells. Lung cancer is the most common type of cancer worldwide in which SETDB1 amplification and H3K9 hypermethylation have been indicated as potential tumourigenesis markers. In contrast, frequent inactivation mutations of SETDB1 have been revealed in mesothelioma, an asbestos-associated, locally aggressive, highly lethal, and notoriously chemotherapy-resistant cancer. Above all, the different statuses of SETDB1 indicate that it may have different biological functions and be a potential diagnostic biomarker and therapeutic target in lung cancer and mesothelioma. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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19 pages, 881 KiB

Open AccessReview

Neutrophils in Tumorigenesis: Missing Targets for Successful Next Generation Cancer Therapies?

by Fabrice Tolle, Viktor Umansky, Jochen Utikal, Stephanie Kreis and Sabrina Bréchard

Int. J. Mol. Sci. 2021, 22(13), 6744; https://doi.org/10.3390/ijms22136744 - 23 Jun 2021

Cited by 17 | Viewed by 4010

Abstract

Neutrophils—once considered as simple killers of pathogens and unexciting for cancer research—are now acknowledged for their role in the process of tumorigenesis. Neutrophils are recruited to the tumor microenvironment where they turn into tumor-associated neutrophils (TANs), and are able to initiate and promote [...] Read more.

Neutrophils—once considered as simple killers of pathogens and unexciting for cancer research—are now acknowledged for their role in the process of tumorigenesis. Neutrophils are recruited to the tumor microenvironment where they turn into tumor-associated neutrophils (TANs), and are able to initiate and promote tumor progression and metastasis. Conversely, anti-tumorigenic properties of neutrophils have been documented, highlighting the versatile nature and high pleiotropic plasticity of these polymorphonuclear leukocytes (PMN-L). Here, we dissect the ambivalent roles of TANs in cancer and focus on selected functional aspects that could be therapeutic targets. Indeed, the critical point of targeting TAN functions lies in the fact that an immunosuppressive state could be induced, resulting in unwanted side effects. A deeper knowledge of the mechanisms linked to diverse TAN functions in different cancer types is necessary to define appropriate therapeutic strategies that are able to induce and maintain an anti-tumor microenvironment. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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26 pages, 1473 KiB

Open AccessReview

Nanotechnology of Tyrosine Kinase Inhibitors in Cancer Therapy: A Perspective

by Eleonora Russo, Andrea Spallarossa, Bruno Tasso, Carla Villa and Chiara Brullo

Int. J. Mol. Sci. 2021, 22(12), 6538; https://doi.org/10.3390/ijms22126538 - 18 Jun 2021

Cited by 22 | Viewed by 4918

Abstract

Nanotechnology is an important application in modern cancer therapy. In comparison with conventional drug formulations, nanoparticles ensure better penetration into the tumor mass by exploiting the enhanced permeability and retention effect, longer blood circulation times by a reduced renal excretion and a decrease [...] Read more.

Nanotechnology is an important application in modern cancer therapy. In comparison with conventional drug formulations, nanoparticles ensure better penetration into the tumor mass by exploiting the enhanced permeability and retention effect, longer blood circulation times by a reduced renal excretion and a decrease in side effects and drug accumulation in healthy tissues. The most significant classes of nanoparticles (i.e., liposomes, inorganic and organic nanoparticles) are here discussed with a particular focus on their use as delivery systems for small molecule tyrosine kinase inhibitors (TKIs). A number of these new compounds (e.g., Imatinib, Dasatinib, Ponatinib) have been approved as first-line therapy in different cancer types but their clinical use is limited by poor solubility and oral bioavailability. Consequently, new nanoparticle systems are necessary to ameliorate formulations and reduce toxicity. In this review, some of the most important TKIs are reported, focusing on ongoing clinical studies, and the recent drug delivery systems for these molecules are investigated. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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19 pages, 363 KiB

Open AccessReview

Ovarian Cancer Immunotherapy and Personalized Medicine

by Susan Morand, Monika Devanaboyina, Hannah Staats, Laura Stanbery and John Nemunaitis

Int. J. Mol. Sci. 2021, 22(12), 6532; https://doi.org/10.3390/ijms22126532 - 18 Jun 2021

Cited by 183 | Viewed by 18290

Abstract

Ovarian cancer response to immunotherapy is limited; however, the evaluation of sensitive/resistant target treatment subpopulations based on stratification by tumor biomarkers may improve the predictiveness of response to immunotherapy. These markers include tumor mutation burden, PD-L1, tumor-infiltrating lymphocytes, homologous recombination deficiency, and neoantigen [...] Read more.

Ovarian cancer response to immunotherapy is limited; however, the evaluation of sensitive/resistant target treatment subpopulations based on stratification by tumor biomarkers may improve the predictiveness of response to immunotherapy. These markers include tumor mutation burden, PD-L1, tumor-infiltrating lymphocytes, homologous recombination deficiency, and neoantigen intratumoral heterogeneity. Future directions in the treatment of ovarian cancer include the utilization of these biomarkers to select ideal candidates. This paper reviews the role of immunotherapy in ovarian cancer as well as novel therapeutics and study designs involving tumor biomarkers that increase the likelihood of success with immunotherapy in ovarian cancer. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

17 pages, 1498 KiB

Open AccessReview

Neurobiology of Cancer: Introduction of New Drugs in the Treatment and Prevention of Cancer

by Boris Mravec

Int. J. Mol. Sci. 2021, 22(11), 6115; https://doi.org/10.3390/ijms22116115 - 6 Jun 2021

Cited by 5 | Viewed by 4690

Abstract

Research on the neurobiology of cancer, which lies at the border of neuroscience and oncology, has elucidated the mechanisms and pathways that enable the nervous system to modulate processes associated with cancer initiation and progression. This research has also shown that several drugs [...] Read more.

Research on the neurobiology of cancer, which lies at the border of neuroscience and oncology, has elucidated the mechanisms and pathways that enable the nervous system to modulate processes associated with cancer initiation and progression. This research has also shown that several drugs which modulate interactions between the nervous system and the tumor micro- and macroenvironments significantly reduced the progression of cancer in animal models. Encouraging results were also provided by prospective clinical trials investigating the effect of drugs that reduce adrenergic signaling on the course of cancer in oncological patients. Moreover, it has been shown that reducing adrenergic signaling might also reduce the incidence of cancer in animal models, as well as in humans. However, even if many experimental and clinical findings have confirmed the preventive and therapeutic potential of drugs that reduce the stimulatory effect of the nervous system on processes related to cancer initiation and progression, several questions remain unanswered. Therefore, the aim of this review is to critically evaluate the efficiency of these drugs and to discuss questions that need to be answered before their introduction into conventional cancer treatment and prevention. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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15 pages, 545 KiB

Open AccessReview

Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors

by Alice Indini, Erika Rijavec and Francesco Grossi

Int. J. Mol. Sci. 2021, 22(9), 4774; https://doi.org/10.3390/ijms22094774 - 30 Apr 2021

Cited by 75 | Viewed by 13647

Abstract

HER2 targeted therapies have significantly improved prognosis of HER2-positive breast and gastric cancer. HER2 overexpression and mutation is the pathogenic driver in non-small cell lung cancer (NSCLC) and colorectal cancer, however, to date, there are no approved HER2-targeted therapies with these indications. Trastuzumab [...] Read more.

HER2 targeted therapies have significantly improved prognosis of HER2-positive breast and gastric cancer. HER2 overexpression and mutation is the pathogenic driver in non-small cell lung cancer (NSCLC) and colorectal cancer, however, to date, there are no approved HER2-targeted therapies with these indications. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody drug conjugate showing significant anti-tumor activity in heavily pre-treated HER2-positive breast and gastric cancer patients. Preliminary data have shown promising objective response rates in patients with HER2-positive NSCLC and colorectal cancer. T-DXd has an acceptable safety profile, however with concerns regarding potentially serious treatment-emergent adverse events. In this review we focus on the pharmacologic characteristics and toxicity profile of T-Dxd, and provide an update on the most recent results of clinical trials of T-DXd in solid tumors. The referenced papers were selected through a PubMed search performed on 16 March 2021 with the following searching terms: T-DXd and breast cancer, or gastric cancer, or non-small cell lung cancer (NSCLC), or colorectal cancer. Oral presentation, abstracts, and posters presented at the American Society of Clinical Oncology (ASCO, Alexandria, VA, USA) 2020 and the European Society for Medical Oncology (ESMO, Lugano, Switzerland) 2020 annual meetings were retrieved for data on T-DXd. We also overview ongoing research and data of combination therapies currently under investigation, which will impact on future therapeutic strategies. Clinicaltrials.gov was searched to identify ongoing clinical trials of T-DXd alone or in combination in solid tumors. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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26 pages, 2623 KiB

Open AccessReview

Anti-Angiogenic Therapy: Current Challenges and Future Perspectives

by Filipa Lopes-Coelho, Filipa Martins, Sofia A. Pereira and Jacinta Serpa

Int. J. Mol. Sci. 2021, 22(7), 3765; https://doi.org/10.3390/ijms22073765 - 5 Apr 2021

Cited by 192 | Viewed by 11630

Abstract

Anti-angiogenic therapy is an old method to fight cancer that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new blood vessels formation. Most of the anti-angiogenic agents approved [...] Read more.

Anti-angiogenic therapy is an old method to fight cancer that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new blood vessels formation. Most of the anti-angiogenic agents approved for cancer treatment rely on targeting vascular endothelial growth factor (VEGF) actions, as VEGF signaling is considered the main angiogenesis promotor. In addition to the control of angiogenesis, these drugs can potentiate immune therapy as VEGF also exhibits immunosuppressive functions. Despite the mechanistic rational that strongly supports the benefit of drugs to stop cancer progression, they revealed to be insufficient in most cases. We hypothesize that the rehabilitation of old drugs that interfere with mechanisms of angiogenesis related to tumor microenvironment might represent a promising strategy. In this review, we deepened research on the molecular mechanisms underlying anti-angiogenic strategies and their failure and went further into the alternative mechanisms that impact angiogenesis. We concluded that the combinatory targeting of alternative effectors of angiogenic pathways might be a putative solution for anti-angiogenic therapies. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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21 pages, 830 KiB

Open AccessReview

CD200:CD200R Interactions and Their Importance in Immunoregulation

by Katarzyna Kotwica-Mojzych, Barbara Jodłowska-Jędrych and Mariusz Mojzych

Int. J. Mol. Sci. 2021, 22(4), 1602; https://doi.org/10.3390/ijms22041602 - 5 Feb 2021

Cited by 65 | Viewed by 9696

Abstract

The molecule CD200, described many years ago as a naturally occurring immunomodulatory agent, capable of regulating inflammation and transplant rejection, has attracted additional interest over the past years with the realization that it may also serve as an important marker for progressive malignancy. [...] Read more.

The molecule CD200, described many years ago as a naturally occurring immunomodulatory agent, capable of regulating inflammation and transplant rejection, has attracted additional interest over the past years with the realization that it may also serve as an important marker for progressive malignancy. A large body of evidence also supports the hypothesis that this molecule can contribute to immunoregulation of, among other diseases, infection, autoimmune disease and allergy. New data have also come to light to characterize the receptors for CD200 (CD200R) and their potential mechanism(s) of action at the biochemical level, as well as the description of a novel natural antagonist of CD200, lacking the NH₂-terminal region of the full-length molecule. Significant controversies exist concerning the relative importance of CD200 as a ligand for all reported CD200Rs. Nevertheless, some progress has been made in the identification of the structural constraints determining the interaction between CD200 and CD200R, and this information has in turn proved of use in developing novel small molecule agonists/antagonists of the interaction. The review below highlights many of these newer findings, and attempts to place them in the broad context of our understanding of the role of CD200-CD200R interactions in a variety of human diseases. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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32 pages, 12812 KiB

Open AccessReview

Anticancer and Immunomodulatory Benefits of Taro (Colocasia esculenta) Corms, an Underexploited Tuber Crop

by Patrícia Ribeiro Pereira, Érika Bertozzi de Aquino Mattos, Anna Carolina Nitzsche Teixeira Fernandes Corrêa, Mauricio Afonso Vericimo and Vania Margaret Flosi Paschoalin

Int. J. Mol. Sci. 2021, 22(1), 265; https://doi.org/10.3390/ijms22010265 - 29 Dec 2020

Cited by 27 | Viewed by 10491

Abstract

Taro corms contain valuable bioactive molecules effective against cancer and cancer-related risk factors, such as carcinogens and biological agents, several pathophysiological conditions, including oxidative stress and inflammation, while controlling metabolic dysfunctions and boosting the immunological response. Such broad effects are achieved by the [...] Read more.

Taro corms contain valuable bioactive molecules effective against cancer and cancer-related risk factors, such as carcinogens and biological agents, several pathophysiological conditions, including oxidative stress and inflammation, while controlling metabolic dysfunctions and boosting the immunological response. Such broad effects are achieved by the taro health-influencing compounds displaying antitumoral, antimutagenic, immunomodulatory, anti-inflammatory, antioxidant, anti-hyperglycemic, and anti-hyperlipidemic activities. Taro bioactivities are attributed to the combination of tarin, taro-4-I polysaccharide, taro polysaccharides 1 and 2 (TPS-1 and TPS-2), A-1/B-2 α-amylase inhibitors, monogalactosyldiacylglycerols (MGDGs), digalactosyldiacylglycerols (DGDGs), polyphenols, and nonphenolic antioxidants. Most of these compounds have been purified and successfully challenged in vitro and in vivo, proving their involvement in the aforementioned activities. Although these health-promoting effects have been recognized since ancient times, as well as other valuable features of taro for food profit, such as hypo-allergenicity, gluten-free, and carbohydrates with medium-glycemic index, taro crop remains underexploited. The popularization of taro intake should be considered a dietary intervention strategy to be applied to improve the overall health status of the organism and as supportive therapy to manage tumorigenesis. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

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