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Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells.

ABSTRACT: Although treatment of prostate cancer has improved over the past several years, taxanes, such as cabazitaxel, remain the only form of effective chemotherapy that improves survival in patients with metastatic castration-resistant prostate cancer. However, the effectiveness of this class of drugs has been associated with various side effects and drug resistance. We previously reported that fisetin, a hydroxyflavone, is a microtubule-stabilizing agent and inhibits prostate cancer cell proliferation, migration, and invasion and suggested its use as an adjuvant for treatment of prostate and other cancer types. In this study, we investigated the effect of fisetin in combination with cabazitaxel with the objective to achieve maximum therapeutic benefit, reduce dose and toxicity, and minimize or delay the induction of drug resistance and metastasis. Our data show for the first time that a combination of fisetin (20 ?mol/L) enhances cabazitaxel (5 nmol/L) and synergistically reduces 22R?1, PC-3M-luc-6, and C4-2 cell viability and metastatic properties with minimal adverse effects on normal prostate epithelial cells. In addition, the combination of fisetin with cabazitaxel was associated with inhibition of proliferation and enhancement of apoptosis. Furthermore, combination treatment resulted in the inhibition of tumor growth, invasion, and metastasis when assessed in two in vivo xenograft mouse models. These results provide evidence that fisetin may have therapeutic benefit for patients with advanced prostate cancer through enhancing the efficacy of cabazitaxel under both androgen-dependent and androgen-independent conditions. This study underscores the benefit of the combination of fisetin with cabazitaxel for the treatment of advanced and resistant prostate cancer and possibly other cancer types. Mol Cancer Ther; 15(12); 2863-74. ©2016 AACR.

SUBMITTER: Mukhtar E

PROVIDER: S-EPMC5136329 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells.

Mukhtar Eiman E Adhami Vaqar Mustafa VM Siddiqui Imtiaz Ahmad IA Verma Ajit Kumar AK Mukhtar Hasan H

Molecular cancer therapeutics 20161007 12

Although treatment of prostate cancer has improved over the past several years, taxanes, such as cabazitaxel, remain the only form of effective chemotherapy that improves survival in patients with metastatic castration-resistant prostate cancer. However, the effectiveness of this class of drugs has been associated with various side effects and drug resistance. We previously reported that fisetin, a hydroxyflavone, is a microtubule-stabilizing agent and inhibits prostate cancer cell proliferation ...[more]

PMID: 27765854

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Project description:BACKGROUND:Despite new drugs, metastatic prostate cancer remains fatal. Growing interest in the latest approved cabazitaxel taxane drug has markedly increased due to the survival benefits conferred when used at an earlier stage of the disease, its promising new therapeutic combination and formulation, and its differential toxicity. Still cabazitaxel's mechanisms of resistance are poorly characterized. The goal of this study was thus to generate a new model of acquired resistance against cabazitaxel in order to unravel cabazitaxel's resistance mechanisms. METHODS:Du145 cells were cultured with increasing concentrations of cabazitaxel, docetaxel/ taxane control or placebo/age-matched control. Once resistance was reached, Epithelial-to-Mesenchymal Translation (EMT) was tested by cell morphology, cell migration, and E/M markers expression profile. Cell transcriptomics were determined by RNA sequencing; related pathways were identified using IPA, PANTHER or KEGG software. The Wnt pathway was analyzed by western blotting, pharmacological and knock-down studies. RESULTS:While age-matched Du145 cells were sensitive to both taxane drugs, docetaxel-resistant cells were only resistant to docetaxel and cabazitaxel-resistant cells showed a partial cross-resistance to both drugs concomitant to EMT. Using RNA-sequencing, the Wnt non-canonical pathway was identified as exclusively activated in cabazitaxel resistant cells while the Wnt canonical pathway was restricted to docetaxel-resistant cells. Cabazitaxel-resistant cells showed a minimal crossover in the Wnt-pathway-related genes linked to docetaxel resistance validating our unique model of acquired resistance to cabazitaxel. Pharmacological and western blot studies confirmed these findings and suggest the implication of the Tyrosine kinase Ror2 receptor in cabazitaxel resistant cells. Variation in Ror2 expression level altered the sensitivity of prostate cancer cells to both drugs identifying a possible new target for taxane resistance. CONCLUSION:Our study represents the first demonstration that while Wnt pathway seems to play an important role in taxanes resistance, Wnt effectors responsible for taxane specificity remain un-identified prompting the need for more studies.

Dataset Information

Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells.

Publications

Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells.

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