title: 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 μmol/L) enhances cabazitaxel (5 nmol/L) and synergistically reduces 22Rν1, 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.
authors.affiliation: Department of Dermatology, University of Wisconsin-Madison, Madison Wisconsin.
authors.forename: Eiman
authors.initials: E
authors.lastname: Mukhtar
authors.affiliation: Department of Dermatology, University of Wisconsin-Madison, Madison Wisconsin.
authors.forename: Vaqar Mustafa
authors.initials: VM
authors.lastname: Adhami
authors.affiliation: Department of Dermatology, University of Wisconsin-Madison, Madison Wisconsin.
authors.forename: Imtiaz Ahmad
authors.initials: IA
authors.lastname: Siddiqui
authors.affiliation: Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Ajit Kumar
authors.initials: AK
authors.lastname: Verma
authors.affiliation: Department of Dermatology, University of Wisconsin-Madison, Madison Wisconsin. hmukhtar@dermatology.wisc.edu.
authors.forename: Hasan
authors.initials: H
authors.lastname: Mukhtar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology*; D016896:Treatment Outcome; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D044948:Flavonols; D043823:Taxoids; C552428:cabazitaxel; C017875:fisetin