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5 pages, 229 KiB

Open AccessEditorial

Advances in Plants-Derived Bioactives for Cancer Treatment

by Natália Cruz-Martins

Cells 2023, 12(8), 1112; https://doi.org/10.3390/cells12081112 - 8 Apr 2023

Cited by 3 | Viewed by 1488

Abstract

Cancer, while a multifactorial chronic disease with an increasing prevalence, has been the subject of intense investigation, not only because of the growing need to find the main triggers that motivate its onset but essentially because of the need to discover increasingly safer [...] Read more.

Cancer, while a multifactorial chronic disease with an increasing prevalence, has been the subject of intense investigation, not only because of the growing need to find the main triggers that motivate its onset but essentially because of the need to discover increasingly safer and effective therapeutic options that have fewer adverse effects and associated toxicity [...] Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

Research

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16 pages, 4023 KiB

Open AccessArticle

Sulforaphane Potentiates Gemcitabine-Mediated Anti-Cancer Effects against Intrahepatic Cholangiocarcinoma by Inhibiting HDAC Activity

by Fumimasa Tomooka, Kosuke Kaji, Norihisa Nishimura, Takahiro Kubo, Satoshi Iwai, Akihiko Shibamoto, Junya Suzuki, Koh Kitagawa, Tadashi Namisaki, Takemi Akahane, Akira Mitoro and Hitoshi Yoshiji

Cells 2023, 12(5), 687; https://doi.org/10.3390/cells12050687 - 22 Feb 2023

Cited by 12 | Viewed by 2788

Abstract

Intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver cancer, has high mortality rates because of its limited treatment options and acquired resistance to chemotherapy. Sulforaphane (SFN), a naturally occurring organosulfur compound found in cruciferous vegetables, exhibits multiple therapeutic properties, such as histone [...] Read more.

Intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver cancer, has high mortality rates because of its limited treatment options and acquired resistance to chemotherapy. Sulforaphane (SFN), a naturally occurring organosulfur compound found in cruciferous vegetables, exhibits multiple therapeutic properties, such as histone deacetylase (HDAC) inhibition and anti-cancer effects. This study assessed the effects of the combination of SFN and gemcitabine (GEM) on human iCCA cell growth. HuCCT-1 and HuH28 cells, representing moderately differentiated and undifferentiated iCCA, respectively, were treated with SFN and/or GEM. SFN concentration dependently reduced total HDAC activity and promoted total histone H3 acetylation in both iCCA cell lines. SFN synergistically augmented the GEM-mediated attenuation of cell viability and proliferation by inducing G2/M cell cycle arrest and apoptosis in both cell lines, as indicated by the cleavage of caspase-3. SFN also inhibited cancer cell invasion and decreased the expression of pro-angiogenic markers (VEGFA, VEGFR2, HIF-1α, and eNOS) in both iCCA cell lines. Notably, SFN effectively inhibited the GEM-mediated induction of epithelial–mesenchymal transition (EMT). A xenograft assay demonstrated that SFN and GEM substantially attenuated human iCCA cell-derived tumor growth with decreased Ki67⁺ proliferative cells and increased TUNEL⁺ apoptotic cells. The anti-cancer effects of every single agent were markedly augmented by concomitant use. Consistent with the results of in vitro cell cycle analysis, G2/M arrest was indicated by increased p21 and p-Chk2 expression and decreased p-Cdc25C expression in the tumors of SFN- and GEM-treated mice. Moreover, treatment with SFN inhibited CD34-positive neovascularization with decreased VEGF expression and GEM-induced EMT in iCCA-derived xenografted tumors. In conclusion, these results suggest that combination therapy with SFN with GEM is a potential novel option for iCCA treatment. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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24 pages, 3029 KiB

Open AccessArticle

Aglianico Grape Seed Semi-Polar Extract Exerts Anticancer Effects by Modulating MDM2 Expression and Metabolic Pathways

by Rossana Cuciniello, Francesco Di Meo, Maria Sulli, Olivia Costantina Demurtas, Mirella Tanori, Mariateresa Mancuso, Clizia Villano, Riccardo Aversano, Domenico Carputo, Alfonso Baldi, Gianfranco Diretto, Stefania Filosa and Stefania Crispi

Cells 2023, 12(2), 210; https://doi.org/10.3390/cells12020210 - 4 Jan 2023

Cited by 6 | Viewed by 2239

Abstract

Grapevine (Vitis vinifera L.) seeds are rich in polyphenols including proanthocyanidins, molecules with a variety of biological effects including anticancer action. We have previously reported that the grape seed semi-polar extract of Aglianico cultivar (AGS) was able to induce apoptosis and decrease [...] Read more.

Grapevine (Vitis vinifera L.) seeds are rich in polyphenols including proanthocyanidins, molecules with a variety of biological effects including anticancer action. We have previously reported that the grape seed semi-polar extract of Aglianico cultivar (AGS) was able to induce apoptosis and decrease cancer properties in different mesothelioma cell lines. Concomitantly, this extract resulted in enriched oligomeric proanthocyanidins which might be involved in determining the anticancer activity. Through transcriptomic and metabolomic analyses, we investigated in detail the anticancer pathway induced by AGS. Transcriptomics analysis and functional annotation allowed the identification of the relevant causative genes involved in the apoptotic induction following AGS treatment. Subsequent biological validation strengthened the hypothesis that MDM2 could be the molecular target of AGS and that it could act in both a p53-dependent and independent manner. Finally, AGS significantly inhibited tumor progression in a xenograft mouse model of mesothelioma, confirming also in vivo that MDM2 could act as molecular player responsible for the AGS antitumor effect. Our findings indicated that AGS, exerting a pro-apoptotic effect by hindering MDM2 pathway, could represent a novel source of anticancer molecules. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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21 pages, 4739 KiB

Open AccessFeature PaperArticle

Genome-Wide Analysis on Transcriptome and Methylome in Prevention of Mammary Tumor Induced by Early Life Combined Botanicals

by Itika Arora, Shizhao Li, Michael R. Crowley, Yuanyuan Li and Trygve O. Tollefsbol

Cells 2023, 12(1), 14; https://doi.org/10.3390/cells12010014 - 21 Dec 2022

Cited by 7 | Viewed by 1851

Abstract

Breast cancer (BC) is the most common malignancy and the second leading cause of cancer death among women in the United States. The consumption of natural dietary components such as broccoli sprouts (BSp) and green tea polyphenols (GTPs) has demonstrated exciting potential in [...] Read more.

Breast cancer (BC) is the most common malignancy and the second leading cause of cancer death among women in the United States. The consumption of natural dietary components such as broccoli sprouts (BSp) and green tea polyphenols (GTPs) has demonstrated exciting potential in reducing the risk of BC through the regulation of epigenetic mechanisms. However, little is known about their impacts on reversing epigenomic aberrations that are centrally involved in the initiation and progression of BC. Previously, we have determined the efficacy of combined BSp and GTPs treatment on the inhibition of the growth of a mammary tumor in a transgenic Her2/neu mouse model. We sought to extend our previous study to identify universal biomarkers that represent common mechanistic changes among different mouse models in response to this dietary regime by including a new transgenic mouse model, C3(1)-SV40 TAg (SV40). As a result, we identified novel target genes that were differentially expressed and methylated in response to dietary botanicals when administered singly (BSp and GTPs) and in combination (BSp + GTPs) in both mouse models. We discovered more differentially expressed and methylated genes in the combination treatment group compared to the singly administered groups. Subsequently, several biological pathways related to epigenetic regulations were identified in response to the combination treatment. Furthermore, when compared to the BSp and GTPs treatment alone, the combinatorial treatment showed a more significant impact on the regulation of the epigenetic modifier activities involved in DNA methylation and histone modifications. Our study provides key insights about the impact of the combined administration of BSp and GTPs on BC using a multi-omics analysis, suggesting a combinatorial approach is more efficacious in preventing and inhibiting BC by impacting key tumor-related genes at transcriptomic and methylomic levels. Our findings could be further extrapolated as a comprehensive source for understanding the epigenetic modifications that are associated with the effects of these dietary botanicals on BC prevention. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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19 pages, 6868 KiB

Open AccessArticle

Tannic Acid, A Hydrolysable Tannin, Prevents Transforming Growth Factor-β-Induced Epithelial–Mesenchymal Transition to Counteract Colorectal Tumor Growth

by Mahassen Barboura, Clarisse Cornebise, François Hermetet, Abderrahmane Guerrache, Mouna Selmi, Abir Salek, Leila Chekir-Ghedira, Virginie Aires and Dominique Delmas

Cells 2022, 11(22), 3645; https://doi.org/10.3390/cells11223645 - 17 Nov 2022

Cited by 7 | Viewed by 2582

Abstract

Despite the medico-surgical progress that has been made in the management of patients with colorectal cancer (CRC), the prognosis at five years remains poor. This resistance of cancer cells partly results from their phenotypic characteristics in connection with the epithelial–mesenchymal transition (EMT). In [...] Read more.

Despite the medico-surgical progress that has been made in the management of patients with colorectal cancer (CRC), the prognosis at five years remains poor. This resistance of cancer cells partly results from their phenotypic characteristics in connection with the epithelial–mesenchymal transition (EMT). In the present study, we have explored the ability of a polyphenol, tannic acid (TA), to counteract CRC cell proliferation and invasion through an action on the EMT. We highlight that TA decreases human SW480 and SW620 CRC cell and murine CT26 CRC cell viability, and TA inhibits their adhesion in the presence of important factors comprising the extracellular matrix, particularly in the presence of collagen type I and IV, and fibronectin. Moreover, these properties were associated with TA’s ability to disrupt CRC cell migration and invasion, which are induced by transforming growth factor-β (TGF-β), as evidence in the video microscopy experiments showing that TA blocks the TGF-β1-induced migration of SW480 and CT26 cells. At the molecular level, TA promotes a reversal of the epithelial–mesenchymal transition by repressing the mesenchymal markers (i.e., Slug, Snail, ZEB1, and N-cadherin) and re-expressing the epithelial markers (i.e., E-cadherin and β-catenin). These effects could result from a disruption of the non-canonical signaling pathway that is induced by TGF-β1, where TA strongly decreases the phosphorylation of extracellular-signal regulated kinase ERK1/2, P38 and the AKT proteins that are well known to contribute to the EMT, the cell motility, and the acquisition of invasive properties by tumor cells. Very interestingly, a preclinical study of mice with subcutaneous murine tumor colon CT26 cells has shown that TA was able to significantly delay the growth of tumors without hepato- and nephrotoxicities. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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13 pages, 3821 KiB

Open AccessArticle

Naturally Occurring Bicoumarin Compound Daphnoretin Inhibits Growth and Induces Megakaryocytic Differentiation in Human Chronic Myeloid Leukemia Cells

by Yu-Chuen Huang, Chun-Ping Huang, Chin-Ping Lin, Kai-Chien Yang, Yu-Jie Lei, Hao-Pei Wang, Yueh-Hsiung Kuo and Yu-Jen Chen

Cells 2022, 11(20), 3252; https://doi.org/10.3390/cells11203252 - 16 Oct 2022

Cited by 6 | Viewed by 2160

Abstract

Daphnoretin extracted from the stem and roots of Wikstroemia indica (L.) C.A. Mey has been shown to possess antiviral and antitumor activities. Herein, we hypothesized that daphnoretin might induce megakaryocytic differentiation, thereby inhibiting the proliferation of cells and serving as a differentiation therapy [...] Read more.

Daphnoretin extracted from the stem and roots of Wikstroemia indica (L.) C.A. Mey has been shown to possess antiviral and antitumor activities. Herein, we hypothesized that daphnoretin might induce megakaryocytic differentiation, thereby inhibiting the proliferation of cells and serving as a differentiation therapy agent for chronic myeloid leukemia (CML). Daphnoretin-treated K562 and HEL cells were examined for growth inhibition, cell morphology, and megakaryocyte-specific markers. Potential mechanisms of megakaryocytic differentiation of daphnoretin-treated K562 cells were evaluated. The results showed that daphnoretin inhibited the growth of K562 and HEL cells in a dose- and time-dependent manner. Flow cytometry analyses revealed that daphnoretin treatment slightly increased the proportion of sub-G1 and polyploid cells compared to that of dimethyl sulfoxide (DMSO)-treated control cells. Morphological examination showed that daphnoretin-treated K562 and HEL cells exhibited enlarged contours and multinucleation as megakaryocytic characteristics compared to DMSO-treated control cells. Daphnoretin treatment also dramatically enhanced the expression of megakaryocytic markers CD61 and CD41. Under optimal megakaryocytic differentiation conditions, daphnoretin increased the phosphorylation of STAT3 but not STAT5. In summary, daphnoretin inhibited cell growth and induced megakaryocytic differentiation in K562 and HEL cells. The efficacy of daphnoretin in vivo and in patients with CML may need further investigations for validation. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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22 pages, 4148 KiB

Open AccessArticle

An Evaluation of the Novel Biological Properties of Diterpenes Isolated from Plectranthus ornatus Codd. In Vitro and In Silico

by Przemysław Sitarek, Tomasz Kowalczyk, Ewelina Synowiec, Anna Merecz-Sadowska, Gabrielle Bangay, Salvatore Princiotto, Tomasz Śliwiński and Patricia Rijo

Cells 2022, 11(20), 3243; https://doi.org/10.3390/cells11203243 - 15 Oct 2022

Cited by 5 | Viewed by 2823

Abstract

Plectranthus ornatus Codd, the genus Plectranthus of the Lamiaceae family, has been used as traditional medicine in Africa, India and Australia. Pharmacological studies show the use of this plant to treat digestive problems. In turn, leaves were used for their antibiotic properties in [...] Read more.

Plectranthus ornatus Codd, the genus Plectranthus of the Lamiaceae family, has been used as traditional medicine in Africa, India and Australia. Pharmacological studies show the use of this plant to treat digestive problems. In turn, leaves were used for their antibiotic properties in some regions of Brazil to treat skin infections. The present study examines the anti-inflammatory, antioxidant and cytotoxic effects of the halimane and labdane diterpenes (11R*,13E)-11-acetoxyhalima-5,13-dien-15-oic acid (HAL) and 1α,6β-diacetoxy-8α,13R*-epoxy-14-labden-11-one (PLEC) and the forskolin-like 1:1 mixture of 1,6-di-O-acetylforskolin and 1,6-di-O-acetyl-9-deoxyforskolin (MRC) isolated from P. ornatus on lung (A549) and leukemia (CCRF-CEM) cancer cell lines, and on normal human retinal pigment epithelial (ARPE-19) cell line in vitro. Additionally, molecular docking and computational approaches were used. ADMET properties were analysed through SwissADME and proTox-II—Prediction. The results indicate that all tested compounds significantly reduced the viability of the cancer cells and demonstrated no cytotoxic effects against the non-neoplastic cell line. The apoptosis indicators showed increased ROS levels for both the tested A549 and CCRF-CEM cancer cell lines after treatment. Furthermore, computational studies found HAL to exhibit moderate antioxidant activity. In addition, selected compounds changed mitochondrial membrane potential (MMP), and increased DNA damage and mitochondrial copy number for the CCRF-CEM cancer cell line; they also demonstrated anti-inflammatory effects on the ARPE-19 normal cell line upon lipopolysaccharide (LPS) treatment, which was associated with the modulation of IL-6, IL-8, TNF-α and GM-CSF genes expression. Docking studies gave indication about the lowest binding energy for 1,6-di-O-acetylforskolin docked into IL-6, TNF-α and GM-CSF, and 1,6-di-O-acetyl-9-deoxyforskolin docked into IL-8. The ADMET studies showed drug-likeness properties for the studied compounds. Thus, halimane and labdane diterpenes isolated from P. ornatus appear to offer biological potential; however, further research is necessary to understand their interactions and beneficial properties. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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19 pages, 3884 KiB

Open AccessFeature PaperArticle

Orobanche crenata Forssk. Extract Affects Human Breast Cancer Cell MCF-7 Survival and Viral Replication

by Carlo Genovese, Adriana Garozzo, Floriana D’Angeli, Giuseppe Antonio Malfa, Francesco Bellia, Barbara Tomasello, Daria Nicolosi, Roberta Malaguarnera, Simone Ronsisvalle, Fiorella Guadagni and Rosaria Acquaviva

Cells 2022, 11(10), 1696; https://doi.org/10.3390/cells11101696 - 19 May 2022

Cited by 5 | Viewed by 2970

Abstract

Background: Breast cancer (BC) is the leading cause of death worldwide. The severity of BC strictly depends on the molecular subtype. The less aggressive hormone-positive subtype is treated with adjuvant endocrine therapy (AET), which causes both physical and psychological side effects. This condition [...] Read more.

Background: Breast cancer (BC) is the leading cause of death worldwide. The severity of BC strictly depends on the molecular subtype. The less aggressive hormone-positive subtype is treated with adjuvant endocrine therapy (AET), which causes both physical and psychological side effects. This condition strongly impacts the adherence and persistence of AET among oncologic patients. Moreover, viral infections also constitute a serious problem for public health. Despite their efficacy, antiviral agents present several therapeutic limits. Accordingly, in the present work, we investigated the antitumor and antiviral activities of Orobanche crenata Forssk. (O. crenata), a parasitic plant, endemic to the Mediterranean basin, traditionally known for its beneficial properties for human health. Methods: The MTT assay was carried out to evaluate the cytotoxic effect of O. crenata leaf extract (OCLE) on human breast cancer cells (MCF-7 and MDA-MB-231) and the primary HFF-1 cell line. The lactic dehydrogenase (LDH) assay was performed on MCF-7 cells to analyze necrotic cell death. The antioxidant effect of OCLE was evaluated by intracellular determination of the reactive oxygen species and thiol groups, by DPPH and ABTS assays. The antiviral activity of OCLE was determined against Poliovirus 1, Echovirus 9, Human respiratory syncytial virus, Adenovirus type 2 and type 5, Coxsackievirus B1 (CoxB1) and B3 (CoxB3), Herpes simplex type 1 (HSV-1) and type 2 (HSV-2), and β-Coronavirus by the plaque reduction assay. Results: The extract, after 24 h of incubation, did not affect MDA-MB-231 and HFF-1 cell viability. However, at the same time point, it showed a dose-dependent inhibitory effect on MCF-7 cells, with an increase in LDH release. OCLE exhibited free radical scavenging activity and significantly increased non-protein thiol levels in MCF-7 cells. OCLE effectively inhibited HSV-1, HSV-2, CoxB1, and CoxB3 replication. Conclusions: The overall results showed an interesting inhibitory effect of OCLE on both MCF-7 cell survival and viral replication. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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15 pages, 2401 KiB

Open AccessArticle

Crocin Inhibits Angiogenesis and Metastasis in Colon Cancer via TNF-α/NF-kB/VEGF Pathways

by Hamid A. Bakshi, Gerry A. Quinn, Mohamed M. Nasef, Vijay Mishra, Alaa A. A. Aljabali, Mohamed El-Tanani, Ángel Serrano-Aroca, Mateus Webba Da Silva, Paul A. McCarron and Murtaza M. Tambuwala

Cells 2022, 11(9), 1502; https://doi.org/10.3390/cells11091502 - 29 Apr 2022

Cited by 64 | Viewed by 6723

Abstract

Angiogenesis and metastasis play pivotal roles in the progression of cancer. We recently discovered that crocin, a dietary carotenoid derived from the Himalayan crocus, inhibited the growth of colon cancer cells. However, the exact role of crocin on the angiogenesis and metastasis in [...] Read more.

Angiogenesis and metastasis play pivotal roles in the progression of cancer. We recently discovered that crocin, a dietary carotenoid derived from the Himalayan crocus, inhibited the growth of colon cancer cells. However, the exact role of crocin on the angiogenesis and metastasis in colorectal cancer remains unclear. In the present study, we demonstrated that crocin significantly reduces the viability of colon cancer cells (HT-29, Caco-2) and human umbilical vein endothelial cells (HUVEC), but was not toxic to human colon epithelial (HCEC) cells. Furthermore, pre-treatment of human carcinoma cells (HT-29 and Caco-2) with crocin inhibited cell migration, invasion, and angiogenesis in concentration -dependent manner. Further studies demonstrated that crocin inhibited TNF-α, NF-κB and VEGF pathways in colon carcinoma cell angiogenesis and metastasis. Crocin also inhibited cell migration, invasion, and tube formation in human umbilical vein endothelial cells (HUVEC) in a concentration -dependent manner. We also observed that crocin significantly reduced the secretion of VEGF and TNF-α induced activation of NF-kB by human colon carcinoma cells. In the absence of TNF-α, a concentration-dependent reduction in NF-kB was observed. Many of these observations were confirmed by in vivo angiogenesis models, which showed that crocin significantly reduced the progression of tumour growth. Collectively, these finding suggest that crocin inhibits angiogenesis and colorectal cancer cell metastasis by targeting NF-kB and blocking TNF-α/NF-κB/VEGF pathways. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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26 pages, 10199 KiB

Open AccessArticle

Lichen Secondary Metabolites Inhibit the Wnt/β-Catenin Pathway in Glioblastoma Cells and Improve the Anticancer Effects of Temozolomide

by Aleksandra Majchrzak-Celińska, Robert Kleszcz, Elżbieta Studzińska-Sroka, Agnieszka Łukaszyk, Anna Szoszkiewicz, Ewelina Stelcer, Karol Jopek, Marcin Rucinski, Judyta Cielecka-Piontek and Violetta Krajka-Kuźniak

Cells 2022, 11(7), 1084; https://doi.org/10.3390/cells11071084 - 23 Mar 2022

Cited by 20 | Viewed by 3167

Abstract

Lichens are a source of secondary metabolites with significant pharmacological potential. Data regarding their possible application in glioblastoma (GBM) treatment are, however, scarce. The study aimed at analyzing the mechanism of action of six lichen secondary metabolites: atranorin, caperatic acid, physodic acid, squamatic [...] Read more.

Lichens are a source of secondary metabolites with significant pharmacological potential. Data regarding their possible application in glioblastoma (GBM) treatment are, however, scarce. The study aimed at analyzing the mechanism of action of six lichen secondary metabolites: atranorin, caperatic acid, physodic acid, squamatic acid, salazinic acid, and lecanoric acid using two- and three-dimensional GBM cell line models. The parallel artificial membrane permeation assay was used to predict the blood-brain barrier penetration ability of the tested compounds. Their cytotoxicity was analyzed using the MTT test on A-172, T98G, and U-138 MG cells. Flow cytometry was applied to the analysis of oxidative stress, cell cycle distribution, and apoptosis, whereas qPCR and microarrays detected the induced transcriptomic changes. Our data confirm the ability of lichen secondary metabolites to cross the blood-brain barrier and exert cytotoxicity against GBM cells. Moreover, the compounds generated oxidative stress, interfered with the cell cycle, and induced apoptosis in T98G cells. They also inhibited the Wnt/β-catenin pathway, and this effect was even stronger in case of a co-treatment with temozolomide. Transcriptomic changes in cancer related genes induced by caperatic acid and temozolomide were the most pronounced. Lichen secondary metabolites, caperatic acid in particular, should be further analyzed as potential anti-GBM agents. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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30 pages, 9044 KiB

Open AccessFeature PaperArticle

Attenuation of Pancreatic Cancer In Vitro and In Vivo via Modulation of Nrf2 and NF-κB Signaling Pathways by Natural Compounds

by Marta Cykowiak, Robert Kleszcz, Małgorzata Kucińska, Jarosław Paluszczak, Hanna Szaefer, Adam Plewiński, Hanna Piotrowska-Kempisty, Marek Murias and Violetta Krajka-Kuźniak

Cells 2021, 10(12), 3556; https://doi.org/10.3390/cells10123556 - 16 Dec 2021

Cited by 16 | Viewed by 3393

Abstract

Pancreatic cancer is a disease in which deregulation of signaling pathways plays a key role, thus searching for their novel modulators is a promising therapeutic strategy. Hence, in this study, the effect of phytochemical combinations on the canonical and non-canonical activation of Nrf2 [...] Read more.

Pancreatic cancer is a disease in which deregulation of signaling pathways plays a key role, thus searching for their novel modulators is a promising therapeutic strategy. Hence, in this study, the effect of phytochemical combinations on the canonical and non-canonical activation of Nrf2 and its interaction with the NF-κB pathway was evaluated in extensively proliferating pancreatic cancer cell line, PSN-1, in comparison to non-cancerous MS1 cells. The activation of Nrf2 and NF-κB, expression of their target genes, and effect on cell survival were assessed in PSN-1 cells. The tumor burden was evaluated in mice carrying xenografts. PSN-1 cells were more sensitive to the tested compounds as compared to the MS1 cell line. Combination of xanthohumol and phenethyl isothiocyanate was more effective than single compounds at decreasing the canonical and non-canonical activation of Nrf2 in PSN-1 cancer cells. Decreased activation of NF-κB, and subsequent reduced cytosolic COX-2 and nuclear STAT3 level indicated their anti-inflammatory and pro-apoptotic activities. In vivo studies showed the partial response in groups treated with xanthohumol or the combination of xanthohumol and phenethyl isothiocyanate. Overall, these results suggest that the combination of xanthohumol and phenethyl isothiocyanate may be a promising therapeutic candidate against pancreatic cancer. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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13 pages, 2843 KiB

Open AccessArticle

In Silico Evaluation of Natural Compounds for an Acidic Extracellular Environment in Human Breast Cancer

by YoungJoon Park, Jaekwang Jeong, Shin Seong and Wonnam Kim

Cells 2021, 10(10), 2673; https://doi.org/10.3390/cells10102673 - 6 Oct 2021

Cited by 5 | Viewed by 3194

Abstract

The survival rates for breast cancer (BC) have improved in recent years, but resistance, metastasis, and recurrence still remain major therapeutic challenges for BC. The acidic tumor microenvironment (TME) has attracted attention because of its association with tumorigenesis, metastasis, drug resistance, and immune [...] Read more.

The survival rates for breast cancer (BC) have improved in recent years, but resistance, metastasis, and recurrence still remain major therapeutic challenges for BC. The acidic tumor microenvironment (TME) has attracted attention because of its association with tumorigenesis, metastasis, drug resistance, and immune surveillance. In this study, we evaluated natural compounds from traditional herbal medicine used to treat cancer that selectively target genes regulated by extracellular acidosis. We integrated four transcriptomic data including BC prognostic data from The Cancer Genome Atlas database, gene expression profiles of MCF-7 cells treated with 102 natural compounds, patterns of gene profiles by acidic condition, and single-cell RNA-sequencing from BC patient samples. Bruceine D (BD) was predicted as having the highest therapeutic potential, having an information gain (IG) score of 0.24, to regulate reprogrammed genes driven by acidosis affecting the survival of BC patients. BD showed the highest IG on EMT (IG score: 0.11) and invasion (IG score: 0.1) compared to the other phenotypes with the CancerSEA database. BD also demonstrated therapeutic potential by interfering with the tumor cell–TME interactions by reducing the amyloid beta precursor protein and CD44 expression. Therefore, BD is a potential candidate to target the acidic TME induced metastatic process in BC. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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17 pages, 4244 KiB

Open AccessArticle

7-Epitaxol Induces Apoptosis and Autophagy in Head and Neck Squamous Cell Carcinoma through Inhibition of the ERK Pathway

by V. Bharath Kumar, Ming-Ju Hsieh, B. Mahalakshmi, Yi-Ching Chuang, Chia-Chieh Lin, Yu-Sheng Lo, Hsin-Yu Ho and Jen-Tsun Lin

Cells 2021, 10(10), 2633; https://doi.org/10.3390/cells10102633 - 2 Oct 2021

Cited by 8 | Viewed by 2762

Abstract

As the main derivative of paclitaxel, 7-Epitaxol is known to a have higher stability and cytotoxicity. However, the anticancer effect of 7-Epitaxol is still unclear. The purpose of this study was to explore the anticancer effects of 7-Epitaxol in squamous cell carcinoma of [...] Read more.

As the main derivative of paclitaxel, 7-Epitaxol is known to a have higher stability and cytotoxicity. However, the anticancer effect of 7-Epitaxol is still unclear. The purpose of this study was to explore the anticancer effects of 7-Epitaxol in squamous cell carcinoma of the head and neck (HNSCC). Our study findings revealed that 7-Epitaxol potently suppressed cell viability in SCC-9 and SCC-47 cells by inducing cell cycle arrest. Flow cytometry and DAPI staining demonstrated that 7-Epitaxol treatment induced cell death, mitochondrial membrane potential and chromatin condensation in OSCC cell lines. The compound regulated the proteins of extrinsic and intrinsic pathways at the highest concentration, and also increased the activation of caspases 3, 8, 9, and PARP in OSCC cell lines. Interestingly, a 7-Epitaxol-mediated induction of LC3-I/II expression and suppression of p62 expression were observed in OSCC cells lines. Furthermore, the MAPK inhibitors indicated that 7-Epitaxol induces apoptosis and autophagy marker proteins (cleaved-PARP and LC3-I/II) by reducing the phosphorylation of ERK1/2. In conclusion, these findings indicate the involvement of 7-Epitaxol in inducing apoptosis and autophagy through ERK1/2 signaling pathway, which identify 7-Epitaxol as a potent cytotoxic agent in HNSCC. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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Review

Jump to: Editorial, Research

21 pages, 1324 KiB

Open AccessReview

by Yuanyuan Ding, Baofang Fan, Cheng Zhu and Zhixiang Chen

Cells 2023, 12(2), 219; https://doi.org/10.3390/cells12020219 - 4 Jan 2023

Cited by 8 | Viewed by 3506

Abstract

Salicylic acid (SA) is a phenolic compound produced by all plants that has an important role in diverse processes of plant growth and stress responses. SA is also the principal metabolite of aspirin and is responsible for many of the anti-inflammatory, cardioprotective and [...] Read more.

Salicylic acid (SA) is a phenolic compound produced by all plants that has an important role in diverse processes of plant growth and stress responses. SA is also the principal metabolite of aspirin and is responsible for many of the anti-inflammatory, cardioprotective and antitumor activities of aspirin. As a result, the number of identified SA targets in both plants and humans is large and continues to increase. These SA targets include catalases/peroxidases, metabolic enzymes, protein kinases and phosphatases, nucleosomal and ribosomal proteins and regulatory and signaling proteins, which mediate the diverse actions of SA in plants and humans. While some of these SA targets and actions are unique to plants or humans, many others are conserved or share striking similarities in the two types of organisms, which underlie a host of common biological processes that are regulated or impacted by SA. In this review, we compare shared and related SA targets and activities to highlight the common nature of actions by SA as a hormone in plants versus a therapeutic agent in humans. The cross examination of SA targets and activities can help identify new actions of SA and better explain their underlying mechanisms in plants and humans. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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22 pages, 2399 KiB

Open AccessReview

Multi-Target Potential of Berberine as an Antineoplastic and Antimetastatic Agent: A Special Focus on Lung Cancer Treatment

by Ijeoma Theresa Achi, Paromita Sarbadhikary, Blassan P. George and Heidi Abrahamse

Cells 2022, 11(21), 3433; https://doi.org/10.3390/cells11213433 - 31 Oct 2022

Cited by 22 | Viewed by 5091

Abstract

Despite therapeutic advancements, lung cancer remains the principal cause of cancer mortality in a global scenario. The increased incidence of tumor reoccurrence and progression and the highly metastatic nature of lung cancer are of great concern and hence require the investigation of novel [...] Read more.

Despite therapeutic advancements, lung cancer remains the principal cause of cancer mortality in a global scenario. The increased incidence of tumor reoccurrence and progression and the highly metastatic nature of lung cancer are of great concern and hence require the investigation of novel therapies and/or medications. Naturally occurring compounds from plants serve as important resources for novel drugs for cancer therapy. Amongst these phytochemicals, Berberine, an alkaloid, has been extensively explored as a potential natural anticancer therapeutic agent. Several studies have shown the effectiveness of Berberine in inhibiting cancer growth and progression mediated via several different mechanisms, which include cell cycle arrest, inducing cell death by apoptosis and autophagy, inhibiting cell proliferation and invasion, as well as regulating the expression of microRNA, telomerase activity, and the tumor microenvironment, which usually varies for different cancer types. In this review, we aim to provide a better understanding of molecular insights of Berberine and its various derivative-induced antiproliferative and antimetastatic effects against lung cancer. In conclusion, the Berberine imparts its anticancer efficacy against lung cancers via modulation of several signaling pathways involved in cancer cell viability and proliferation, as well as migration, invasion, and metastasis. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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34 pages, 18090 KiB

Open AccessReview

A Review of the Pharmacological Potential of Spatholobus suberectus Dunn on Cancer

by Feng Zhang, Kumar Ganesan, Qingqing Liu and Jianping Chen

Cells 2022, 11(18), 2885; https://doi.org/10.3390/cells11182885 - 15 Sep 2022

Cited by 11 | Viewed by 3258

Abstract

Spatholobus suberectus Dunn (SSD) has been extensively employed in Traditional Chinese Medicine to treat several ailments. SSD and its active compounds are effective therapeutic agents for treating a variety of diseases with negligible side effects. Therefore, we aimed to investigate its phytochemistry, pharmacology, [...] Read more.

Spatholobus suberectus Dunn (SSD) has been extensively employed in Traditional Chinese Medicine to treat several ailments. SSD and its active compounds are effective therapeutic agents for treating a variety of diseases with negligible side effects. Therefore, we aimed to investigate its phytochemistry, pharmacology, and potential therapeutic effects exclusively in cancer prevention and treatment. Phytochemical and pharmacological information was collected and arranged in a rational order. SSD has been frequently attributed to having antioxidant, anti-diabetic, anti-inflammatory, hematopoietic, neuroprotective, antimicrobial, and anticancer properties. Evidence has indicated that the bioactive constituents in SSD have attracted increasing scientific attention due to their preventive role in cancers. Further, the present review provides the current information on the health implications of SSD, thus allowing for future clinical trials to explore its restorative benefits. All data of in vitro and animal investigations of SSD, as well as its effect on human health, were obtained from an electronic search and library database. The diverse pharmacological potential of SSD provides an opportunity for preclinical drug discovery, and this comprehensive review strongly indicates that SSD is an excellent anti-tumorigenic agent that modulates or prevents breast cancer. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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20 pages, 3585 KiB

Open AccessReview

The Role of Natural Products and Their Multitargeted Approach to Treat Solid Cancer

by Naoshad Muhammad, Darksha Usmani, Mohammad Tarique, Huma Naz, Mohammad Ashraf, Ramesh Raliya, Shams Tabrez, Torki A. Zughaibi, Ahdab Alsaieedi, Israa J. Hakeem and Mohd Suhail

Cells 2022, 11(14), 2209; https://doi.org/10.3390/cells11142209 - 15 Jul 2022

Cited by 47 | Viewed by 5477

Abstract

Natural products play a critical role in the discovery and development of numerous drugs for the treatment of various types of cancer. These phytochemicals have demonstrated anti-carcinogenic properties by interfering with the initiation, development, and progression of cancer through altering various mechanisms such [...] Read more.

Natural products play a critical role in the discovery and development of numerous drugs for the treatment of various types of cancer. These phytochemicals have demonstrated anti-carcinogenic properties by interfering with the initiation, development, and progression of cancer through altering various mechanisms such as cellular proliferation, differentiation, apoptosis, angiogenesis, and metastasis. Treating multifactorial diseases, such as cancer with agents targeting a single target, might lead to limited success and, in many cases, unsatisfactory outcomes. Various epidemiological studies have shown that the steady consumption of fruits and vegetables is intensely associated with a reduced risk of cancer. Since ancient period, plants, herbs, and other natural products have been used as healing agents. Likewise, most of the medicinal ingredients accessible today are originated from the natural resources. Regardless of achievements, developing bioactive compounds and drugs from natural products has remained challenging, in part because of the problem associated with large-scale sequestration and mechanistic understanding. With significant progress in the landscape of cancer therapy and the rising use of cutting-edge technologies, we may have come to a crossroads to review approaches to identify the potential natural products and investigate their therapeutic efficacy. In the present review, we summarize the recent developments in natural products-based cancer research and its application in generating novel systemic strategies with a focus on underlying molecular mechanisms in solid cancer. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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48 pages, 2133 KiB

Open AccessReview

Role of Plant-Derived Active Constituents in Cancer Treatment and Their Mechanisms of Action

by Abdul Waheed Khan, Mariya Farooq, Muhammad Haseeb and Sangdun Choi

Cells 2022, 11(8), 1326; https://doi.org/10.3390/cells11081326 - 13 Apr 2022

Cited by 33 | Viewed by 5224

Abstract

Despite significant technological advancements in conventional therapies, cancer remains one of the main causes of death worldwide. Although substantial progress has been made in the control and treatment of cancer, several limitations still exist, and there is scope for further advancements. Several adverse [...] Read more.

Despite significant technological advancements in conventional therapies, cancer remains one of the main causes of death worldwide. Although substantial progress has been made in the control and treatment of cancer, several limitations still exist, and there is scope for further advancements. Several adverse effects are associated with modern chemotherapy that hinder cancer treatment and lead to other critical disorders. Since ancient times, plant-based medicines have been employed in clinical practice and have yielded good results with few side effects. The modern research system and advanced screening techniques for plants’ bioactive constituents have enabled phytochemical discovery for the prevention and treatment of challenging diseases such as cancer. Phytochemicals such as vincristine, vinblastine, paclitaxel, curcumin, colchicine, and lycopene have shown promising anticancer effects. Discovery of more plant-derived bioactive compounds should be encouraged via the exploitation of advanced and innovative research techniques, to prevent and treat advanced-stage cancers without causing significant adverse effects. This review highlights numerous plant-derived bioactive molecules that have shown potential as anticancer agents and their probable mechanisms of action and provides an overview of in vitro, in vivo and clinical trial studies on anticancer phytochemicals. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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27 pages, 3437 KiB

Open AccessReview

The Promising Therapeutic and Preventive Properties of Anthocyanidins/Anthocyanins on Prostate Cancer

by Javad Mottaghipisheh, Amir Hossein Doustimotlagh, Cambyz Irajie, Nader Tanideh, Alireza Barzegar and Aida Iraji

Cells 2022, 11(7), 1070; https://doi.org/10.3390/cells11071070 - 22 Mar 2022

Cited by 27 | Viewed by 6178

Abstract

As water-soluble flavonoid derivatives, anthocyanidins and anthocyanins are the plants pigments mostly rich in berries, pomegranate, grapes, and dark color fruits. Many bioactivity properties of these advantageous phytochemicals have been reported; among them, their significant abilities in the suppression of tumor cells are [...] Read more.

As water-soluble flavonoid derivatives, anthocyanidins and anthocyanins are the plants pigments mostly rich in berries, pomegranate, grapes, and dark color fruits. Many bioactivity properties of these advantageous phytochemicals have been reported; among them, their significant abilities in the suppression of tumor cells are of the promising therapeutic features, which have recently attracted great attention. The prostate malignancy, is considered the 2nd fatal and the most distributed cancer type in men worldwide. The present study was designated to gather the preclinical and clinical studies evaluating potencies of anthocyanidins/anthocyanins for the treatment and prevention of this cancer type for the first time. In general, findings confirm that the anthocyanins (especifically cyanidin-3-O-glucoside) indicated higher activity against prostatic neoplasms compared to their correlated anthocyanidins (e.g., delphinidin); in which potent anti-inflammatory, apoptosis, and anti-proliferative activities were analyzed. Complementary anti-prostate cancer assessment of diverse naturally occurred anthocyanidins/anthocyanins and their synthetically optimized derivatives through preclinical experiments and eventually confirmed by clinical trials can promisingly lead to discover natural-based chemotherapeutic drug options. Full article

(This article belongs to the Special Issue Advances in Plants-Derived Bioactives for Cancer Treatment)

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