Therapeutic Potential of Gnetin C in Prostate Cancer: A Pre-Clinical Study

Natural stilbenes have gained significant attention in the scientific community owing to their potential anticancer effects against prostate cancer. We recently reported that Gnetin C, a resveratrol (Res) dimer, demonstrated more potent inhibition of metastasis-associated protein 1/v-ets avian erythroblastosis virus E26 oncogene homolog 2 (MTA1/ETS2) axis in prostate cancer cell lines than other stilbenes. In this study, we investigated in vivo antitumor effects of Gnetin C in two doses (50 and 25 mg/kg, i.p.) using PC3M-Luc subcutaneous xenografts and compared these to Res and pterostilbene (Pter). We found that while vehicle-treated mice revealed rapid tumor progression, compounds-treated mice showed noticeable delay in tumor growth. Gnetin C in 50 mg/kg dose demonstrated the most potent tumor inhibitory effects. Gnetin C in 25 mg/kg dose exhibited tumor inhibitory effects comparable with Pter in 50 mg/kg dose. Consistent with the effective antitumor effects, Gnetin C-treated tumors showed reduced mitotic activity and angiogenesis and a significant increase in apoptosis compared to all the other groups. The data suggest that Gnetin C is more potent in slowing tumor progression in prostate cancer xenografts than Res or Pter. Taken together, we demonstrated, for the first time, that Gnetin C is a lead compound among stilbenes for effectively blocking prostate cancer progression in vivo.

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Alantolactone: A Natural Plant Extract as a Potential Therapeutic Agent for Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2021.781033 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuan Cai ◽

Kewa Gao ◽

Bi Peng ◽

Zhijie Xu ◽

Jinwu Peng ◽

...

Keyword(s):

Molecular Mechanisms ◽

Cancer Colorectal ◽

Therapeutic Potential ◽

Inhibitory Effects ◽

Cytotoxic Effects ◽

Cancer Breast ◽

Anticancer Effects ◽

Inula Helenium

Alantolactone (ALT) is a natural compound extracted from Chinese traditional medicine Inula helenium L. with therapeutic potential in the treatment of various diseases. Recently, in vitro and in vivo studies have indicated cytotoxic effects of ALT on various cancers, including liver cancer, colorectal cancer, breast cancer, etc. The inhibitory effects of ALT depend on several cancer-associated signaling pathways and abnormal regulatory factors in cancer cells. Moreover, emerging studies have reported several promising strategies to enhance the oral bioavailability of ALT, such as combining ALT with other herbs and using ALT-entrapped nanostructured carriers. In this review, studies on the anti-tumor roles of ALT are mainly summarized, and the underlying molecular mechanisms of ALT exerting anticancer effects on cells investigated in animal-based studies are also discussed.

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Macrophage-derived cholesterol contributes to therapeutic resistance in prostate cancer

10.1101/2021.03.24.436480 ◽

2021 ◽

Author(s):

Asmaa El-Kenawi ◽

William Dominguez-Viqueira ◽

Min Liu ◽

Shivanshu Awasthi ◽

Aysenur Keske ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Nuclear Translocation ◽

Cholesterol Metabolism ◽

Therapeutic Potential ◽

Cholesterol Homeostasis ◽

Castration Resistant Prostate Cancer ◽

Macrophage Depletion

Tumor-associated macrophages are key immune cells associated with cancer progression. Here we sought to determine the role of macrophages in castration-resistant prostate cancer (CRPC) using a syngeneic model that reflected the mutational landscape of the disease. A transcriptomic analysis of CRPC tumors following macrophage depletion revealed lower molecular signatures for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. Since cholesterol is the precursor of the five major classes of steroid hormones, we reasoned that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Indeed, macrophage depletion reduced the levels of androgens within prostate tumors and restricted androgen receptor (AR) nuclear localization in vitro and in vivo. Macrophages were cholesterol rich and had the ability to transfer cholesterol to tumor cells in vitro, and AR nuclear translocation was inhibited by activation of Liver X Receptor (LXR)-β, the master regulator of cholesterol homeostasis. Finally, combining macrophage depletion with androgen deprivation therapy increased survival, supporting the therapeutic potential of targeting macrophages in CRPC.

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Phytosomal Curcumin Elicits Anti-tumor Properties Through Suppression of Angiogenesis, Cell Proliferation and Induction of Oxidative Stress in Colorectal Cancer

Current Pharmaceutical Design ◽

10.2174/1381612825666190110145151 ◽

2019 ◽

Vol 24 (39) ◽

pp. 4626-4638 ◽

Cited By ~ 13

Author(s):

Reyhaneh Moradi-Marjaneh ◽

Seyed M. Hassanian ◽

Farzad Rahmani ◽

Seyed H. Aghaee-Bakhtiari ◽

Amir Avan ◽

...

Keyword(s):

Oxidative Stress ◽

Colorectal Cancer ◽

Therapeutic Potential ◽

Vegf Signaling ◽

Anticancer Effects ◽

Inhibition Of Angiogenesis ◽

Underlying Mechanisms ◽

Apoptotic Activity

Background: Colorectal cancer (CRC) is one of the most common causes of cancer-associated mortality in the world. Anti-tumor effect of curcumin has been shown in different cancers; however, the therapeutic potential of novel phytosomal curcumin, as well as the underlying molecular mechanism in CRC, has not yet been explored. Methods: The anti-proliferative, anti-migratory and apoptotic activity of phytosomal curcumin in CT26 cells was assessed by MTT assay, wound healing assay and Flow cytometry, respectively. Phytosomal curcumin was also tested for its in-vivo activity in a xenograft mouse model of CRC. In addition, oxidant/antioxidant activity was examined by DCFH-DA assay in vitro, measurement of malondialdehyde (MDA), Thiol and superoxidedismutase (SOD) and catalase (CAT) activity and also evaluation of expression levels of Nrf2 and GCLM by qRT-PCR in tumor tissues. In addition, the effect of phytosomal curcumin on angiogenesis was assessed by the measurement of VEGF-A and VEGFR-1 and VEGF signaling regulatory microRNAs (miRNAs) in tumor tissue. Results: Phytosomal curcumin exerts anti-proliferative, anti-migratory and apoptotic activity in-vitro. It also decreases tumor growth and augmented 5-fluorouracil (5-FU) anti-tumor effect in-vivo. In addition, our data showed that induction of oxidative stress and inhibition of angiogenesis through modulation of VEGF signaling regulatory miRNAs might be underlying mechanisms by which phytosomal curcumin exerted its antitumor effect. Conclusion: Our data confirmed this notion that phytosomal curcumin administrates anticancer effects and can be used as a complementary treatment in clinical settings.

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The Anticancer Effects of Flavonoids through miRNAs Modulations in Triple-Negative Breast Cancer

Nutrients ◽

10.3390/nu13041212 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1212

Author(s):

Getinet M. Adinew ◽

Equar Taka ◽

Patricia Mendonca ◽

Samia S. Messeha ◽

Karam F. A. Soliman

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Therapeutic Potential ◽

Biological Activities ◽

Therapeutic Option ◽

Mesenchymal Transition ◽

Anticancer Effects

Triple- negative breast cancer (TNBC) incidence rate has regularly risen over the last decades and is expected to increase in the future. Finding novel treatment options with minimum or no toxicity is of great importance in treating or preventing TNBC. Flavonoids are new attractive molecules that might fulfill this promising therapeutic option. Flavonoids have shown many biological activities, including antioxidant, anti-inflammatory, and anticancer effects. In addition to their anticancer effects by arresting the cell cycle, inducing apoptosis, and suppressing cancer cell proliferation, flavonoids can modulate non-coding microRNAs (miRNAs) function. Several preclinical and epidemiological studies indicate the possible therapeutic potential of these compounds. Flavonoids display a unique ability to change miRNAs’ levels via different mechanisms, either by suppressing oncogenic miRNAs or activating oncosuppressor miRNAs or affecting transcriptional, epigenetic miRNA processing in TNBC. Flavonoids are not only involved in the regulation of miRNA-mediated cancer initiation, growth, proliferation, differentiation, invasion, metastasis, and epithelial-to-mesenchymal transition (EMT), but also control miRNAs-mediated biological processes that significantly impact TNBC, such as cell cycle, immune system, mitochondrial dysregulation, modulating signaling pathways, inflammation, and angiogenesis. In this review, we highlighted the role of miRNAs in TNBC cancer progression and the effect of flavonoids on miRNA regulation, emphasizing their anticipated role in the prevention and treatment of TNBC.

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In vivo CRISPR inactivation of Fos promotes prostate cancer progression by altering the associated AP-1 subunit Jun

Oncogene ◽

10.1038/s41388-021-01724-6 ◽

2021 ◽

Vol 40 (13) ◽

pp. 2437-2447

Author(s):

Maria Riedel ◽

Martin F. Berthelsen ◽

Huiqiang Cai ◽

Jakob Haldrup ◽

Michael Borre ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Prostate Cancer Progression

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Metformin and Niclosamide Synergistically Suppress Wnt and YAP in APC-Mutated Colorectal Cancer

Cancers ◽

10.3390/cancers13143437 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3437

Author(s):

Hee Eun Kang ◽

Yoojeong Seo ◽

Jun Seop Yun ◽

Sang Hyun Song ◽

Dawool Han ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Progression ◽

Therapeutic Strategy ◽

Target Gene ◽

Advanced Colorectal Cancer ◽

Therapeutic Potential ◽

Cancer Stemness ◽

Reciprocal Regulation ◽

Canonical Wnt

The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic niclosamide is an effective inhibitor of Wnt and is now in a phase II trial for advanced colorectal cancer (CRC) patients. We found that Axin2, an authentic target gene of canonical Wnt, acts as aYAP phosphorylation activator in APC-mutated CRC. While niclosamide effectively suppresses Wnt, it also inhibits Hippo, limiting its therapeutic potential for CRC. To overcome this limitation, we utilized metformin, a clinically available AMPK activator. This combinatory approach not only suppresses canonical Wnt activity, but also inhibits YAP activity in CRC cancer cells and in patient-derived cancer organoid through the suppression of cancer stemness. Further, combinatory oral administration suppressed in vivo tumorigenesis and the cancer progression of APC-MIN mice models. Our observations provide not only a reciprocal link between Wnt and Hippo, but also clinically available novel therapeutics that are able to target Wnt and YAP in APC-mutated CRC.

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Dandelion Root and Lemongrass Extracts Induce Apoptosis, Enhance Chemotherapeutic Efficacy, and Reduce Tumour Xenograft Growth In Vivo in Prostate Cancer

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/2951428 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Christopher Nguyen ◽

Ali Mehaidli ◽

Kiruthika Baskaran ◽

Sahibjot Grewal ◽

Alaina Pupulin ◽

...

Keyword(s):

Prostate Cancer ◽

Root Extract ◽

Natural Health Products ◽

Anticancer Efficacy ◽

Adjuvant Therapies ◽

Anticancer Effects ◽

Health Products ◽

Xenograft Models ◽

Pharmaceutical Uses

Many conventional chemotherapies have indicated side effects due to a lack of treatment specificity and are thus not suitable for long-term usage. Natural health products are well-tolerated and safe for consumption, and some have pharmaceutical uses particularly for their anticancer effects. We have previously reported the anticancer efficacy of dandelion (Taraxacum officinale) root and lemongrass (Cymbopogon citratus) extracts. However, their efficacy on prostate cancer and their interactions with standard chemotherapeutics have not been studied to determine if they will be suitable for adjuvant therapies. If successful, these extracts could potentially be used in conjunction with chemotherapeutics to minimize the risk of drug-related toxicity and enhance the efficacy of the treatment. We have demonstrated that both dandelion root extract (DRE) and lemongrass extract (LGE) exhibit selective anticancer activity. Importantly, DRE and LGE addition to the chemotherapeutics taxol and mitoxantrone was determined to enhance the induction of apoptosis when compared to individual chemotherapy treatment alone. Further, DRE and LGE were able to significantly reduce the tumour burden in prostate cancer xenograft models when administered orally, while also being well-tolerated. Thus, the implementation of these well-tolerated extracts in adjuvant therapies could be a selective and efficacious approach to prostate cancer treatment.

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Synergistic Targeting of PI3K/AKT Pathway and Androgen Receptor Axis Significantly Delays Castration-Resistant Prostate Cancer Progression In Vivo

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-13-0032 ◽

2013 ◽

Vol 12 (11) ◽

pp. 2342-2355 ◽

Cited By ~ 75

Author(s):

Christian Thomas ◽

Francois Lamoureux ◽

Claire Crafter ◽

Barry R. Davies ◽

Eliana Beraldi ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Progression ◽

Akt Pathway ◽

Prostate Cancer Progression ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

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Azacitidine improves antitumor effects of docetaxel and cisplatin in aggressive prostate cancer models

Endocrine Related Cancer ◽

10.1677/erc-08-0130 ◽

2009 ◽

Vol 16 (2) ◽

pp. 401-413 ◽

Cited By ~ 49

Author(s):

Claudio Festuccia ◽

Giovanni Luca Gravina ◽

Anna Maria D'Alessandro ◽

Paola Muzi ◽

Danilo Millimaggi ◽

...

Keyword(s):

Prostate Cancer ◽

Synergistic Effects ◽

Disease Stage ◽

Growth Delay ◽

Complete Regression ◽

Antitumor Effects ◽

Aggressive Prostate Cancer ◽

Cancer Models ◽

Hormone Refractory

One of the major obstacles in the treatment of hormone-refractory prostate cancer (HRPC) is the development of chemoresistant tumors. The aim of this study is to evaluate the role of azacitidine as chemosensitizing agent in association with docetaxel (DTX) and cisplatin using two models of aggressive prostate cancer, the 22rv1, and PC3 cell lines. Azacitidine shows antiproliferative effects associated with increased proportion of cells in G0/G1 and evident apoptosis in 22rv1 cells and increased proportion of cells in G2/M phase with the absence of acute cell killing in PC3 cells. In vivo, azacitidine (0.8 mg/kg i.p.) reduced tumor proliferation and induced apoptosis in both xenografts upmodulating the expression of p16INKA, Bax, Bak, p21/WAF1, and p27/KIP1, and inhibiting the activation of Akt activity and the expression of cyclin D1, Bcl-2, and Bcl-XL. In vitro treatments with azacitidine lead to upregulation of cleaved caspase 3 and PARP. BCl2 antagonists, such as HA-14-1, enhanced the effects of azacitidine in these two prostate cancer models. In addition, azacitidine showed synergistic effects with both DTX and cisplatin. In vivo this agent caused tumor growth delay without complete regression in xenograft systems. Azacitidine sensitized PC3 and 22rv1 xenografts to DTX and cisplatin treatments. These combinations were also tolerable in mice and superior to either agent alone. As DTX is the standard first-line chemotherapy for HRPC, the development of DTX-based combination therapies is of great interest in this disease stage. Our results provide a rationale for clinical trials on combination treatments with azacitidine in patients with hormone-refractory and chemoresistant prostate tumors.

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