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14 pages, 948 KiB

Open AccessArticle

Eugenol Exerts Apoptotic Effect and Modulates the Sensitivity of HeLa Cells to Cisplatin and Radiation

by Moustafa Fathy, Michael Atef Fawzy, Henning Hintzsche, Toshio Nikaido, Thomas Dandekar and Eman M. Othman

Molecules 2019, 24(21), 3979; https://doi.org/10.3390/molecules24213979 - 3 Nov 2019

Cited by 67 | Viewed by 5733

Abstract

Eugenol is a phytochemical present in different plant products, e.g., clove oil. Traditionally, it is used against a number of different disorders and it was suggested to have anticancer activity. In this study, the activity of eugenol was evaluated in a human cervical [...] Read more.

Eugenol is a phytochemical present in different plant products, e.g., clove oil. Traditionally, it is used against a number of different disorders and it was suggested to have anticancer activity. In this study, the activity of eugenol was evaluated in a human cervical cancer (HeLa) cell line and cell proliferation was examined after treatment with various concentrations of eugenol and different treatment durations. Cytotoxicity was tested using lactate dehydrogenase (LDH) enzyme leakage. In order to assess eugenol’s potential to act synergistically with chemotherapy and radiotherapy, cell survival was calculated after eugenol treatment in combination with cisplatin and X-rays. To elucidate its mechanism of action, caspase-3 activity was analyzed and the expression of various genes and proteins was checked by RT-PCR and western blot analyses. Eugenol clearly decreased the proliferation rate and increased LDH release in a concentration- and time-dependent manner. It showed synergistic effects with cisplatin and X-rays. Eugenol increased caspase-3 activity and the expression of Bax, cytochrome c (Cyt-c), caspase-3, and caspase-9 and decreased the expression of B-cell lymphoma (Bcl)-2, cyclooxygenase-2 (Cox-2), and interleukin-1 beta (IL-1β) indicating that eugenol mainly induced cell death by apoptosis. In conclusion, eugenol showed antiproliferative and cytotoxic effects via apoptosis and also synergism with cisplatin and ionizing radiation in the human cervical cancer cell line. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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11 pages, 5764 KiB

Open AccessArticle

Efficacy of a Bispecific Antibody Co-Targeting VEGFA and Ang-2 in Combination with Chemotherapy in a Chemoresistant Colorectal Carcinoma Xenograft Model

by Thomas Mueller, Juana Freystein, Henrike Lucas and Hans-Joachim Schmoll

Molecules 2019, 24(16), 2865; https://doi.org/10.3390/molecules24162865 - 7 Aug 2019

Cited by 23 | Viewed by 3834

Abstract

Vascular endothelial growth factor (VEGF) inhibition by the addition of bevacizumab to the chemotherapy regimen of metastatic colorectal cancer leads to an improved outcome. However, anti-angiogenic tumor therapy targeting a single factor may be limited by complementary mechanisms. Angiopoietin-2 (Ang-2, ANGPT2) is another [...] Read more.

Vascular endothelial growth factor (VEGF) inhibition by the addition of bevacizumab to the chemotherapy regimen of metastatic colorectal cancer leads to an improved outcome. However, anti-angiogenic tumor therapy targeting a single factor may be limited by complementary mechanisms. Angiopoietin-2 (Ang-2, ANGPT2) is another important factor that cooperates with VEGF to drive tumor angiogenesis. It was shown that high Ang-2 levels are associated with a poor clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy. Therefore, combined inhibition of VEGF and Ang-2 was supposed to improve anti-angiogenic therapy. Here, we evaluated the efficacy of a bispecific antibody (CrossMab) co-targeting VEGF and Ang-2 in combination with chemotherapy in a chemoresistant colorectal carcinoma model. Antitumor activity was evaluated in athymic nude mice bearing subcutaneous DLD1 xenograft tumors and treated with anti-VEGF (B20), anti-Ang-2 (LC06) and anti-VEGF/Ang-2 (CrossMab) antibodies. Chemotherapy consisted of 5-FU and irinotecan. Resected tumors were analyzed immunohistochemically. First, an impact of targeting each single factor but also a clear advantage of co-targeting both factors could be demonstrated. Accordingly, tumor tissue showed strong staining for VEGF and Ang-2. Chemotherapy alone was less effective. Efficient tumor growth inhibition could be achieved by treatment with anti-VEGF/chemotherapy, single CrossMab and CrossMab/chemotherapy, which resulted in 3 out of 10, 6 out of 10 and 10 out of 10 complete responses, respectively, during seven weeks. Complete retarded tumors were characterized by massive intratumoral necrosis surrounded by layers of vital tumor cells and connective tissue with CD31-positive vessels at the periphery. In some cases, a distinct feature known as vessel co-option could be observed. In conclusion, the data from this model clearly support the strategy of co-targeting VEGF and Ang-2 and further demonstrate the beneficial impact of co-treatment with chemotherapy. The clear superiority of the CrossMab-containing regimen compared to clinical standard anti-VEGF/chemotherapy warrants further analyses in other models. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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13 pages, 2383 KiB

Open AccessArticle

CA-170 – A Potent Small-Molecule PD-L1 Inhibitor or Not?

by Bogdan Musielak, Justyna Kocik, Lukasz Skalniak, Katarzyna Magiera-Mularz, Dominik Sala, Miroslawa Czub, Malgorzata Stec, Maciej Siedlar, Tad A. Holak and Jacek Plewka

Molecules 2019, 24(15), 2804; https://doi.org/10.3390/molecules24152804 - 1 Aug 2019

Cited by 110 | Viewed by 11659

Abstract

CA-170 is currently the only small-molecule modulator in clinical trials targeting PD-L1 and VISTA proteins – important negative checkpoint regulators of immune activation. The reported therapeutic results to some extent mimic those of FDA-approved monoclonal antibodies overcoming the limitations of the high production [...] Read more.

CA-170 is currently the only small-molecule modulator in clinical trials targeting PD-L1 and VISTA proteins – important negative checkpoint regulators of immune activation. The reported therapeutic results to some extent mimic those of FDA-approved monoclonal antibodies overcoming the limitations of the high production costs and adverse effects of the latter. However, no conclusive biophysical evidence proving the binding to hPD-L1 has ever been presented. Using well-known in vitro methods: NMR binding assay, HTRF and cell-based activation assays, we clearly show that there is no direct binding between CA-170 and PD-L1. To strengthen our reasoning, we performed control experiments on AUNP-12 – a 29-mer peptide, which is a precursor of CA-170. Positive controls consisted of the well-documented small-molecule PD-L1 inhibitors: BMS-1166 and peptide-57. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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15 pages, 3403 KiB

Open AccessArticle

Anti-Multiple Myeloma Potential of Secondary Metabolites from Hibiscus sabdariffa

by Alessio Malacrida, Valeria Cavalloro, Emanuela Martino, Arianna Cassetti, Gabriella Nicolini, Roberta Rigolio, Guido Cavaletti, Barbara Mannucci, Francesca Vasile, Marcello Di Giacomo, Simona Collina and Mariarosaria Miloso

Molecules 2019, 24(13), 2500; https://doi.org/10.3390/molecules24132500 - 9 Jul 2019

Cited by 20 | Viewed by 5453

Abstract

Multiple myeloma (MM) belongs to hematological cancers and its incidence is increasing worldwide. Despite recent advances in its therapy, MM still causes many deaths every year. In fact, current therapies sometimes fail and are associated with severe adverse effects, including neurotoxicity. As a [...] Read more.

Multiple myeloma (MM) belongs to hematological cancers and its incidence is increasing worldwide. Despite recent advances in its therapy, MM still causes many deaths every year. In fact, current therapies sometimes fail and are associated with severe adverse effects, including neurotoxicity. As a part of our ongoing efforts to discover new potential therapies against MM, we prepared Hibiscus sabdariffa extracts obtained by a microwave-assisted solvent extraction and investigate their activity by in vitro assays on the RPMI-8226 cell line. The bioguided fractionation of the crude ethanolic extract allowed the identification of HsFC as the most effective extract. We assessed cell viability (MTT and Tripan blue test), cell migration (Boyden chamber assay), and neurotoxicity (DRG neurotoxicity assay). The promising results prompted us to further fractionate HsFC and we obtained two molecules effective against RPMI-8226 cells without neurotoxic effects at their active concentrations. Moreover, both compounds are able to significantly reduce cell migration. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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16 pages, 2855 KiB

Open AccessArticle

The Up-Regulation of Oxidative Stress as a Potential Mechanism of Novel MAO-B Inhibitors for Glioblastoma Treatment

by Guya Diletta Marconi, Marialucia Gallorini, Simone Carradori, Paolo Guglielmi, Amelia Cataldi and Susi Zara

Molecules 2019, 24(10), 2005; https://doi.org/10.3390/molecules24102005 - 25 May 2019

Cited by 24 | Viewed by 4093

Abstract

Gliomas are malignant brain tumors characterized by rapid spread and growth into neighboring tissues and graded I–IV by the World Health Organization. Glioblastoma is the fastest growing and most devastating IV glioma. The aim of this paper is to evaluate the biological effects [...] Read more.

Gliomas are malignant brain tumors characterized by rapid spread and growth into neighboring tissues and graded I–IV by the World Health Organization. Glioblastoma is the fastest growing and most devastating IV glioma. The aim of this paper is to evaluate the biological effects of two potent and selective Monoamine Oxidase B (MAO-B) inhibitors, Cmp3 and Cmp5, in C6 glioma cells and in CTX/TNA2 astrocytes in terms of cell proliferation, apoptosis occurrence, inflammatory events and cell migration. These compounds decrease C6 glioma cells viability sparing normal astrocytes. Cell cycle analysis, the Mitochondrial Membrane Potential (MMP) and Reactive Oxygen Species (ROS) production were detected, revealing that Cmp3 and Cmp5 induce a G1 or G2/M cell cycle arrest, as well as a MMP depolarization and an overproduction of ROS; moreover, they inhibit the expression level of inducible nitric oxide synthase 2, thus contributing to fatal drug-induced oxidative stress. Cmp5 notably reduces glioma cell migration via down-regulating Matrix Metalloproteinases 2 and 9. This study demonstrated that our novel MAO-B inhibitors increase the oxidative stress level resulting in a cell cycle arrest and markedly reduces glioma cells migration thus reinforcing the hypothesis of a critical role-played by MAO-B in mediating oncogenesis in high-grade gliomas. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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14 pages, 7977 KiB

Open AccessArticle

Discovery of 2-(1-(3-(4-Chloroxyphenyl)-3-oxo- propyl)pyrrolidine-3-yl)-1H-benzo[d]imidazole-4-carboxamide: A Potent Poly(ADP-ribose) Polymerase (PARP) Inhibitor for Treatment of Cancer

by Rui Min, Weibin Wu, Mingzhong Wang, Lin Tang, Dawei Chen, Huan Zhao, Cunlong Zhang and Yuyang Jiang

Molecules 2019, 24(10), 1901; https://doi.org/10.3390/molecules24101901 - 17 May 2019

Cited by 16 | Viewed by 4979

Abstract

A series of benzimidazole carboxamide derivatives have been synthesized and characterized by ¹H-NMR, ¹³C-NMR and HRMS. PARP inhibition assays and cellular proliferation assays have also been carried out. Compounds 5cj and 5cp exhibited potential anticancer activities with IC₅₀ values of [...] Read more.

A series of benzimidazole carboxamide derivatives have been synthesized and characterized by ¹H-NMR, ¹³C-NMR and HRMS. PARP inhibition assays and cellular proliferation assays have also been carried out. Compounds 5cj and 5cp exhibited potential anticancer activities with IC₅₀ values of about 4 nM against both PARP-1 and PARP-2, similar to the reference drug veliparib. The two compounds also displayed slightly better in vitro cytotoxicities against MDA-MB-436 and CAPAN-1 cell lines than veliparib and olaparib, with values of 17.4 µM and 11.4 µM, 19.8 µM and 15.5 µM, respectively. The structure-activity relationship based on molecular docking was discussed as well. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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14 pages, 9639 KiB

Open AccessArticle

RA-XII Suppresses the Development and Growth of Liver Cancer by Inhibition of Lipogenesis via SCAP-dependent SREBP Supression

by Di Guo, Yurong Wang, Jing Wang, Lihua Song, Zhe Wang, Bingyu Mao and Ninghua Tan

Molecules 2019, 24(9), 1829; https://doi.org/10.3390/molecules24091829 - 12 May 2019

Cited by 13 | Viewed by 3928

Abstract

Lipogenesis plays a critical role in the growth and metastasis of tumors, which is becoming an attractive target for anti-tumor drugs. RA-XII, one of the cyclopeptide glycosides isolated from Rubia yunnanensis, exerts anti-tumor effects on liver cancer. However, the underlying mechanisms are [...] Read more.

Lipogenesis plays a critical role in the growth and metastasis of tumors, which is becoming an attractive target for anti-tumor drugs. RA-XII, one of the cyclopeptide glycosides isolated from Rubia yunnanensis, exerts anti-tumor effects on liver cancer. However, the underlying mechanisms are not clear. In the present study, the effects of RA-XII on lipogenesis were evaluated and the underlying mechanisms were investigated. The results indicated that RA-XII strongly inhibited tumor growth and lipogenesis (triglycerides and lipid droplets) in HepG2 cells, and the expression of key factors involved in lipogenesis (SREBP, SCD, FASN) was also obviously downregulated. Further investigation showed that the anti-tumor effects of RA-XII were attenuated by SREBP knockdown. Moreover, RA-XII downregulated the expression of SREBP cleavage-activating protein (SCAP), an upstream regulator of SREBP, and siRNA of SCAP prevented its restrained effects on tumor growth and lipogenesis. In addition, the in vivo experiment showed that RA-XII strongly restrained the lipogenesis and growth of liver tumor in nude mice xenograft model. Taken together, these results indicate that RA-XII suppresses the liver cancer growth by inhibition of lipogenesis via SCAP-dependent SREBP suppression. The findings reveal the potentials of RA-XII to be used in a novel therapeutic approach for treating liver cancer. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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16 pages, 2318 KiB

Open AccessArticle

Diclofenac-Derived Hybrids for Treatment of Actinic Keratosis and Squamous Cell Carcinoma

by Silvia Tampucci, Sara Carpi, Maria Digiacomo, Beatrice Polini, Stefano Fogli, Susi Burgalassi, Marco Macchia, Paola Nieri, Clementina Manera and Daniela Monti

Molecules 2019, 24(9), 1793; https://doi.org/10.3390/molecules24091793 - 9 May 2019

Cited by 13 | Viewed by 4914

Abstract

In this work, hybrid compounds 1–4 obtained by conjugation of the non-steroidal anti-inflammatory drug diclofenac, with natural molecules endowed with antioxidant and antiproliferative activity were prepared. The antiproliferative activity of these hybrids was evaluated on immortalized human keratinocyte (HaCaT) cells stimulated [...] Read more.

In this work, hybrid compounds 1–4 obtained by conjugation of the non-steroidal anti-inflammatory drug diclofenac, with natural molecules endowed with antioxidant and antiproliferative activity were prepared. The antiproliferative activity of these hybrids was evaluated on immortalized human keratinocyte (HaCaT) cells stimulated with epidermal growth factor (EGF), an actinic keratosis (AK) model, and on human squamous cell carcinoma (SCC) cells (A431). Hybrid 1 presented the best activity in both cell models. Self-assembling surfactant nanomicelles have been chosen as the carrier to drive the hybrid 1 into the skin; the in vitro permeation through and penetration into pig ear skin have been evaluated. Among the nanostructured formulations tested, Nano3Hybrid20 showed a higher tendency of the hybrid 1 to be retained in the skin rather than permeating it, with a desirable topical and non-systemic action. On these bases, hybrid 1 may represent an attractive lead scaffold for the development of new treatments for AK and SCC. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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16 pages, 3245 KiB

Open AccessArticle

Extracts from Cell Suspension Cultures of Strawberry (Fragaria x ananassa Duch): Cytotoxic Effects on Human Cancer Cells

by Simona Lucioli, Fabio Pastorino, Paolo Nota, Giulia Ballan, Andrea Frattarelli, Alessia Fabbri, Cinzia Forni and Emilia Caboni

Molecules 2019, 24(9), 1738; https://doi.org/10.3390/molecules24091738 - 4 May 2019

Cited by 8 | Viewed by 4039

Abstract

Natural compounds are emerging as agents for the treatment of malignant diseases. We previously showed that extracts from in vitro cell suspension cultures of strawberry reduced murine melanoma cell proliferation, as shown for fruit extracts. In this work, chromatographic, mass spectrometric, and spectrophotometric [...] Read more.

Natural compounds are emerging as agents for the treatment of malignant diseases. We previously showed that extracts from in vitro cell suspension cultures of strawberry reduced murine melanoma cell proliferation, as shown for fruit extracts. In this work, chromatographic, mass spectrometric, and spectrophotometric analyses were carried out to identify the bioactive compound exerting the detected cytotoxic activity. Moreover, aiming to confirm the anti-proliferative activity of the extracts against both paediatric and adult human tumors, cytotoxic experiments were performed on neuroblastoma, colon, and cervix carcinoma cell lines. Extracts from in vitro cell suspension cultures of strawberry induced a statistically significant reduction of cell growth in all the tumor cell lines tested. Interestingly, human fibroblasts from healthy donors were not subjected to this cytotoxic effect, highlighting the importance of further preclinical investigations. The accurate mass measurement, fragmentation patterns, and characteristic mass spectra and mass losses, together with the differences in chromatographic retention times and absorbance spectra, led us to hypothesize that the compound acting as an anti-proliferative agent could be a novel acetal dihydrofurofuran derivative (C₈H₁₀O₃, molecular mass 154.0630 amu) Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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23 pages, 2642 KiB

Open AccessArticle

Design and Synthesis of Novel Anti-Proliferative Emodin Derivatives and Studies on their Cell Cycle Arrest, Apoptosis Pathway and Migration

by Kun Yang, Ming-Ji Jin, Zhe-Shan Quan and Hu-Ri Piao

Molecules 2019, 24(5), 884; https://doi.org/10.3390/molecules24050884 - 2 Mar 2019

Cited by 23 | Viewed by 4595

Abstract

Emodin is a cell arrest and apoptosis-inducing compound that is widely distributed in different plants (rhubarb, aloe), lichens and terrestrial fungi, and also isolated from marine-derived fungi and marine sponge-associated fungi. In this study, we designed and synthesized a novel series of emodin [...] Read more.

Emodin is a cell arrest and apoptosis-inducing compound that is widely distributed in different plants (rhubarb, aloe), lichens and terrestrial fungi, and also isolated from marine-derived fungi and marine sponge-associated fungi. In this study, we designed and synthesized a novel series of emodin derivatives by binding emodin to an amino acid using linkers of varying lengths and composition, and evaluated their anti-proliferative activities using HepG2 cells (human hepatic carcinoma), MCF-7 cells (human breast cancer) and human normal liver L02 cells. Most of these derivatives showed moderate to potent anti-proliferative activities. Notably, compound 7a exhibited potent anti-proliferative activity against HepG2 cells with the half maximal inhibitory concentration (IC₅₀) value of 4.95 µM, which was enhanced 8.8-fold compared to the parent compound emodin (IC₅₀ = 43.87 µM), and it also exhibited better selective anti-proliferative activity and specificity than emodin. Moreover, further experiments demonstrated that compound 7a displayed a significant efficacy of inducing apoptosis through mitochondrial pathway via release of cytochrome c from mitochondria and subsequent activation of caspase-9 and caspase-3, inducing cell arrest at G0/G1 phase, as well as suppression of cell migration of tumor cells. The preliminary results suggested that compound 7a could be a promising lead compound for the discovery of novel anti-tumor drugs and has the potential for further investigations as an anti-cancer drug. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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16 pages, 3542 KiB

Open AccessArticle

Induction of Cell Death in Human A549 Cells Using 3-(Quinoxaline-3-yl) Prop-2-ynyl Methanosulphonate and 3-(Quinoxaline-3-yl) Prop-2-yn-1-ol

by Mixo Aunny Sibiya, Lerato Raphoko, Dikgale Mangokoana, Raymond Makola, Winston Nxumalo and Thabe Moses Matsebatlela

Molecules 2019, 24(3), 407; https://doi.org/10.3390/molecules24030407 - 23 Jan 2019

Cited by 13 | Viewed by 3890

Abstract

Despite major advancements in the development of various chemotherapeutic agents, treatment for lung cancer remains costly, ineffective, toxic to normal non-cancerous cells, and still hampered by a high level of remissions. A novel cohort of quinoxaline derivatives designed to possess a wide spectrum [...] Read more.

Despite major advancements in the development of various chemotherapeutic agents, treatment for lung cancer remains costly, ineffective, toxic to normal non-cancerous cells, and still hampered by a high level of remissions. A novel cohort of quinoxaline derivatives designed to possess a wide spectrum of biological activities was synthesized with promising targeted and selective anticancer drug activity. Hence, this study was aimed at determining in vitro anticancer activity effects of a newly synthesized class of 3-(quinoxaline-3-yl) prop-2-ynyl quinoxaline derivatives on A549 lung cancer cells. An assessment of the quinoxaline derivatives ferric reducing power, free radical scavenging activity, cytotoxic activity, and ability to induce reactive oxygen species (ROS) production was performed using the Ferric Reducing Antioxidant Power (FRAP), 2,2-diphenyl-1-picryl-hydrazyl (DPPH), 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and 2’,7’-dichlorodihydrofluorescein diacetate (H₂DCFDA) assays, respectively. The ability of the quinoxaline derivatives to induce apoptosis in A549 cells was assessed using the Acridine Orange/Ethidium Bromide (AO/EB) and Annexin V-FITC/Dead Cell Assay. Of the four quinoxaline derivatives tested, 3-(quinoxaline-3-yl) prop-2-ynyl methanosulphate (LA-39B) and 3-(quinoxaline-3-yl) prop-2-yn-1-ol (LA-55) displayed a dose-dependent reducing power, free-radical scavenging activity, inhibition of cell viability, and stimulation of ROS production which was accompanied by induction of apoptosis in A549 lung cancer cells. None of the quinoxaline derivatives induced cell death or ROS production in non-cancerous Raw 267.4 macrophage cells. Cytotoxicity was observed in A549 lung cancer, HeLa cervical cancer, and MCF-7 breast cancer cells albeit inhibition was more pronounced in A549 cells. The results of the study suggest that 3-(quinoxaline-3-yl) prop-2-ynyl methanosulphate and 3-(quinoxaline-3-yl) prop-2-yn-1-ol induce apoptotic cell death in A549 lung cancer cells. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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24 pages, 5079 KiB

Open AccessArticle

Design and Synthesis of C-19 Isosteviol Derivatives as Potent and Highly Selective Antiproliferative Agents

by Tian Luan, Li-Hua Cao, Hao Deng, Qing-Kun Shen, Yu-Shun Tian and Zhe-Shan Quan

Molecules 2019, 24(1), 121; https://doi.org/10.3390/molecules24010121 - 30 Dec 2018

Cited by 10 | Viewed by 4033

Abstract

Six series of novel isosteviol derivatives; modified in the C-19 position; were synthesized; and their antiproliferative activity was evaluated against three human cancer cell lines (HCT-116; BEL-7402; HepG2) and the human L02 normal cell line in vitro. Most of the derivatives tested here [...] Read more.

Six series of novel isosteviol derivatives; modified in the C-19 position; were synthesized; and their antiproliferative activity was evaluated against three human cancer cell lines (HCT-116; BEL-7402; HepG2) and the human L02 normal cell line in vitro. Most of the derivatives tested here exhibited improved antiproliferative activity with high selectivity when compared with the parent compound isosteviol and the positive control drug 5-fluorouracil. Among these derivatives; compound 5d exhibited the most potent antiproliferative activity and commendable selectivity between cancer and normal cells. In addition; compound 5d inhibited the colony formation of HCT-116 cells in a concentration-dependent manner. Further studies revealed that compound 5d arrested the HCT-116 cell cycle in the S phase; and western blot analysis demonstrated the mechanism may be correlated with a change in the expression of cyclin A; cyclin B1; and cyclin E1. Furthermore; the results of a docking study that involved placing compound 5d into the CDK2/cyclin A binding site revealed that its mode of action was possibly as a CDK2/cyclin A inhibitor. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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20 pages, 2448 KiB

Open AccessArticle

Synthesis and Evaluation of 3-Substituted-4-(quinoxalin-6-yl) Pyrazoles as TGF-β Type I Receptor Kinase Inhibitors

by Li-Min Zhao, Zhen Guo, Yi-Jie Xue, Jun Zhe Min, Wen-Jing Zhu, Xiang-Yu Li, Hu-Ri Piao and Cheng Hua Jin

Molecules 2018, 23(12), 3369; https://doi.org/10.3390/molecules23123369 - 19 Dec 2018

Cited by 19 | Viewed by 3911

Abstract

The transforming growth factor-β (TGF-β), in which overexpression has been associated with various diseases, has become an attractive molecular target for the treatment of cancers. Thirty-two quinoxaline-derivatives of 3-substituted-4-(quinoxalin-6-yl) pyrazoles 14a–d, 15a–d, 16a–d, 17a [...] Read more.

The transforming growth factor-β (TGF-β), in which overexpression has been associated with various diseases, has become an attractive molecular target for the treatment of cancers. Thirty-two quinoxaline-derivatives of 3-substituted-4-(quinoxalin-6-yl) pyrazoles 14a–d, 15a–d, 16a–d, 17a–d, 18a–d, 19a–d, 25a, 25b, 25d, 26a, 26b, 26d, 27b, and 27d were synthesized and evaluated for their activin TGF-β type I receptor kinase and p38α mitogen activated protein (MAP) kinase inhibitory activity in enzymatic assays. Among these compounds, the most active compound 19b inhibited TGF-β type I receptor kinase phosphorylation with an IC₅₀ value of 0.28 µM, with 98% inhibition at 10 µM. Compound 19b also had good selectivity index of >35 against p38α MAP kinase, with 9.0-fold more selective than clinical candidate, compound 3 (LY-2157299). A molecular docking study was performed to identify the mechanism of action of the synthesized compounds and their good binding interactions were observed. ADMET prediction of good active compounds showed that these ones possess good pharmacokinetics and drug-likeness behavior. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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13 pages, 3558 KiB

Open AccessArticle

Somatostatin Receptors as Molecular Targets in Human Uveal Melanoma

by Kristof Harda, Zsuzsanna Szabo, Erzsebet Szabo, Gabor Olah, Klara Fodor, Csaba Szasz, Gabor Mehes, Andrew V. Schally and Gabor Halmos

Molecules 2018, 23(7), 1535; https://doi.org/10.3390/molecules23071535 - 26 Jun 2018

Cited by 5 | Viewed by 3918

Abstract

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with an incidence of 4–5 cases per million. The prognosis of UM is very poor. In the present study, our aim was to investigate the expression of mRNA and protein for [...] Read more.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with an incidence of 4–5 cases per million. The prognosis of UM is very poor. In the present study, our aim was to investigate the expression of mRNA and protein for somatostatin receptor types-1, -2, -3, -4, -5 (SSTR-1–5) in human UM tissue samples and in OCM-1 and OCM-3 human UM cell lines by qRT-PCR, western blot and ligand competition assay. The mRNA for SSTR-2 showed markedly higher expression in UM tissues than SSTR-5. The presence of SSTRs was demonstrated in 70% of UM specimens using ligand competition assay and both human UM models displayed specific high affinity SSTRs. Among the five SSTRs, the mRNA investigated for SSTR-2 and SSTR-5 receptors was strongly expressed in both human UM cell lines, SSTR-5 showing the highest expression. The presence of the SSTR-2 and SSTR-5 receptor proteins was confirmed in both cell lines by western blot. In summary, the expression of somatostatin receptors in human UM specimens and in OCM-1 and OCM-3 human UM cell lines suggests that they could serve as a potential molecular target for therapy of UM using modern powerful cytotoxic SST analogs targeting SSTR-2 and SSTR-5 receptors. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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16 pages, 1315 KiB

Open AccessArticle

Pyridine-Ureas as Potential Anticancer Agents: Synthesis and In Vitro Biological Evaluation

by Mohamed El-Naggar, Hadia Almahli, Hany S. Ibrahim, Wagdy M. Eldehna and Hatem A. Abdel-Aziz

Molecules 2018, 23(6), 1459; https://doi.org/10.3390/molecules23061459 - 15 Jun 2018

Cited by 65 | Viewed by 6552

Abstract

In our endeavor towards the development of effective anticancer agents, a novel series of pyridine-ureas 8a–n were synthesized. All the newly prepared derivatives were evaluated in vitro for their growth inhibitory activity towards the proliferation of breast cancer MCF-7 cell line. [...] Read more.

In our endeavor towards the development of effective anticancer agents, a novel series of pyridine-ureas 8a–n were synthesized. All the newly prepared derivatives were evaluated in vitro for their growth inhibitory activity towards the proliferation of breast cancer MCF-7 cell line. Compounds 8e and 8n were found to be the most active congeners against MCF-7 cells (IC₅₀ = 0.22 and 1.88 µM after 48 h treatment; 0.11 and 0.80 µM after 72 h treatment, respectively) with increased activity compared to the reference drug doxorubicin (IC₅₀ = 1.93 µM). Moreover, eight selected pyridines 8b, 8d, 8e, 8i, 8j and 8l–n were evaluated for their in vitro anticancer activity according to the US-NCI protocol. Pyridines 8b and 8e proved to be the most effective anticancer agents in the NCI assay with mean inhibition = 43 and 49%, respectively. Both 8b and 8e exhibited anti-proliferative activity against all tested cancer cell lines from all subpanels growth inhibition (GI for 8b; 12–78%, GI for 8e; 15–91%). Pyridines 8b and 8e were screened in vitro for their inhibitory activity against VEGFR-2. Both compounds inhibited VEGFR-2 at micromolar IC₅₀ values 5.0 ± 1.91 and 3.93 ± 0.73 µM, respectively. The most active pyridines were filtered according to the Lipinski and Veber rules and all of them passed these filters. Finally, several ADME descriptors were predicted for the active pyridines through a theoretical kinetic study. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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Review

Jump to: Research

32 pages, 2195 KiB

Open AccessReview

Nasal Drug Delivery of Anticancer Drugs for the Treatment of Glioblastoma: Preclinical and Clinical Trials

by Franciele Aline Bruinsmann, Gustavo Richter Vaz, Aline de Cristo Soares Alves, Tanira Aguirre, Adriana Raffin Pohlmann, Silvia Stanisçuaski Guterres and Fabio Sonvico

Molecules 2019, 24(23), 4312; https://doi.org/10.3390/molecules24234312 - 26 Nov 2019

Cited by 83 | Viewed by 10773

Abstract

Glioblastoma (GBM) is the most lethal form of brain tumor, being characterized by the rapid growth and invasion of the surrounding tissue. The current standard treatment for glioblastoma is surgery, followed by radiotherapy and concurrent chemotherapy, typically with temozolomide. Although extensive research has [...] Read more.

Glioblastoma (GBM) is the most lethal form of brain tumor, being characterized by the rapid growth and invasion of the surrounding tissue. The current standard treatment for glioblastoma is surgery, followed by radiotherapy and concurrent chemotherapy, typically with temozolomide. Although extensive research has been carried out over the past years to develop a more effective therapeutic strategy for the treatment of GBM, efforts have not provided major improvements in terms of the overall survival of patients. Consequently, new therapeutic approaches are urgently needed. Overcoming the blood–brain barrier (BBB) is a major challenge in the development of therapies for central nervous system (CNS) disorders. In this context, the intranasal route of drug administration has been proposed as a non-invasive alternative route for directly targeting the CNS. This route of drug administration bypasses the BBB and reduces the systemic side effects. Recently, several formulations have been developed for further enhancing nose-to-brain transport, mainly with the use of nano-sized and nanostructured drug delivery systems. The focus of this review is to provide an overview of the strategies that have been developed for delivering anticancer compounds for the treatment of GBM while using nasal administration. In particular, the specific properties of nanomedicines proposed for nose-to-brain delivery will be critically evaluated. The preclinical and clinical data considered supporting the idea that nasal delivery of anticancer drugs may represent a breakthrough advancement in the fight against GBM. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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27 pages, 2734 KiB

Open AccessReview

Advances in the Understanding of Skin Cancer: Ultraviolet Radiation, Mutations, and Antisense Oligonucleotides as Anticancer Drugs

by Kateryna V. Laikova, Volodymyr V. Oberemok, Alisa M. Krasnodubets, Nikita V. Gal’chinsky, Refat Z. Useinov, Ilya A. Novikov, Zenure Z. Temirova, Mikhail V. Gorlov, Nikita A. Shved, Vadim V. Kumeiko, Tatiana P. Makalish, Evgeniya Y. Bessalova, Iryna I. Fomochkina, Andrey S. Esin, Mikhail E. Volkov and Anatoly V. Kubyshkin

Molecules 2019, 24(8), 1516; https://doi.org/10.3390/molecules24081516 - 17 Apr 2019

Cited by 81 | Viewed by 9871

Abstract

Skin cancer has always been and remains the leader among all tumors in terms of occurrence. One of the main factors responsible for skin cancer, natural and artificial UV radiation, causes the mutations that transform healthy cells into cancer cells. These mutations inactivate [...] Read more.

Skin cancer has always been and remains the leader among all tumors in terms of occurrence. One of the main factors responsible for skin cancer, natural and artificial UV radiation, causes the mutations that transform healthy cells into cancer cells. These mutations inactivate apoptosis, an event required to avoid the malignant transformation of healthy cells. Among these deadliest of cancers, melanoma and its ‘younger sister’, Merkel cell carcinoma, are the most lethal. The heavy toll of skin cancers stems from their rapid progression and the fact that they metastasize easily. Added to this is the difficulty in determining reliable margins when excising tumors and the lack of effective chemotherapy. Possibly the biggest problem posed by skin cancer is reliably detecting the extent to which cancer cells have spread throughout the body. The initial tumor is visible and can be removed, whereas metastases are invisible to the naked eye and much harder to eliminate. In our opinion, antisense oligonucleotides, which can be used in the form of targeted ointments, provide real hope as a treatment that will eliminate cancer cells near the tumor focus both before and after surgery. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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19 pages, 2816 KiB

Open AccessReview

DHFR Inhibitors: Reading the Past for Discovering Novel Anticancer Agents

by Maria Valeria Raimondi, Ornella Randazzo, Mery La Franca, Giampaolo Barone, Elisa Vignoni, Daniela Rossi and Simona Collina

Molecules 2019, 24(6), 1140; https://doi.org/10.3390/molecules24061140 - 22 Mar 2019

Cited by 163 | Viewed by 13561

Abstract

Dihydrofolate reductase inhibitors are an important class of drugs, as evidenced by their use as antibacterial, antimalarial, antifungal, and anticancer agents. Progress in understanding the biochemical basis of mechanisms responsible for enzyme selectivity and antiproliferative effects has renewed the interest in antifolates for [...] Read more.

Dihydrofolate reductase inhibitors are an important class of drugs, as evidenced by their use as antibacterial, antimalarial, antifungal, and anticancer agents. Progress in understanding the biochemical basis of mechanisms responsible for enzyme selectivity and antiproliferative effects has renewed the interest in antifolates for cancer chemotherapy and prompted the medicinal chemistry community to develop novel and selective human DHFR inhibitors, thus leading to a new generation of DHFR inhibitors. This work summarizes the mechanism of action, chemical, and anticancer profile of the DHFR inhibitors discovered in the last six years. New strategies in DHFR drug discovery are also provided, in order to thoroughly delineate the current landscape for medicinal chemists interested in furthering this study in the anticancer field. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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10 pages, 235 KiB

Open AccessReview

Vitamin C as a Modulator of the Response to Cancer Therapy

by Wiktoria Blaszczak, Wojciech Barczak, Julia Masternak, Przemysław Kopczyński, Anatoly Zhitkovich and Błażej Rubiś

Molecules 2019, 24(3), 453; https://doi.org/10.3390/molecules24030453 - 28 Jan 2019

Cited by 69 | Viewed by 13836

Abstract

Ascorbic acid (vitamin C) has been gaining attention as a potential treatment for human malignancies. Various experimental studies have shown the ability of pharmacological doses of vitamin C alone or in combinations with clinically used drugs to exert beneficial effects in various models [...] Read more.

Ascorbic acid (vitamin C) has been gaining attention as a potential treatment for human malignancies. Various experimental studies have shown the ability of pharmacological doses of vitamin C alone or in combinations with clinically used drugs to exert beneficial effects in various models of human cancers. Cytotoxicity of high doses of vitamin C in cancer cells appears to be related to excessive reactive oxygen species generation and the resulting suppression of the energy production via glycolysis. A hallmark of cancer cells is a strongly upregulated aerobic glycolysis, which elevates its relative importance as a source of ATP (Adenosine 5′-triphosphate). Aerobic glycolysis is maintained by a highly increased uptake of glucose, which is made possible by the upregulated expression of its transporters, such as GLUT-1, GLUT-3, and GLUT-4. These proteins can also transport the oxidized form of vitamin C, dehydroascorbate, permitting its preferential uptake by cancer cells with the subsequent depletion of critical cellular reducers as a result of ascorbate formation. Ascorbate also has a potential to affect other aspects of cancer cell metabolism due to its ability to promote reduction of iron(III) to iron(II) in numerous cellular metalloenzymes. Among iron-dependent dioxygenases, important targets for stimulation by vitamin C in cancer include prolyl hydroxylases targeting the hypoxia-inducible factors HIF-1/HIF-2 and histone and DNA demethylases. Altered metabolism of cancer cells by vitamin C can be beneficial by itself and promote activity of specific drugs. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

19 pages, 872 KiB

Open AccessReview

Mitochondria-Targeting Small Molecules Effectively Prevent Cardiotoxicity Induced by Doxorubicin

by Wei Shi, Hongkuan Deng, Jianyong Zhang, Ying Zhang, Xiufang Zhang and Guozhen Cui

Molecules 2018, 23(6), 1486; https://doi.org/10.3390/molecules23061486 - 19 Jun 2018

Cited by 26 | Viewed by 7007

Abstract

Doxorubicin (Dox) is a chemotherapeutic agent widely used for the treatment of numerous cancers. However, the clinical use of Dox is limited by its unwanted cardiotoxicity. Mitochondrial dysfunction has been associated with Dox-induced cardiotoxicity. To mitigate Dox-related cardiotoxicity, considerable successful examples of a [...] Read more.

Doxorubicin (Dox) is a chemotherapeutic agent widely used for the treatment of numerous cancers. However, the clinical use of Dox is limited by its unwanted cardiotoxicity. Mitochondrial dysfunction has been associated with Dox-induced cardiotoxicity. To mitigate Dox-related cardiotoxicity, considerable successful examples of a variety of small molecules that target mitochondria to modulate Dox-induced cardiotoxicity have appeared in recent years. Here, we review the related literatures and discuss the evidence showing that mitochondria-targeting small molecules are promising cardioprotective agents against Dox-induced cardiac events. Full article

(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)

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