title: Kava components down-regulate expression of AR and AR splice variants and reduce growth in patient-derived prostate cancer xenografts in mice.
abstract: Men living in Fiji and drinking kava have low incidence of prostate cancer (PCa). However, the PCa incidence among Fijian men who had migrated to Australia, increased by 5.1-fold. We therefore examined the potential effects of kava root extracts and its active components (kavalactones and flavokawains) on PCa growth and androgen receptor (AR) expression. PCa cell lines (LNCaP, LAPC-4, 22Rv1, C4-2B, DU145 and PC-3) with different AR expression, and a transformed prostate myofibroblast cell line (WPMY-1), were treated with a commercial kava extract, kavalactones (kawain, 5'6'-dehydrokawain, yangonin, methysticin) and flavokawain B. Expression of AR and its target genes (PSA and TMPRSS2) was examined. Two novel patient-derived PCa xenograft models from high grade PCa specimens were established by implanting the specimens into nude mice and passing tumor pieces through subcutaneous injection in nude mice, and then treated with kava extract and flavokawain B to examine their effects on tumor growth, AR expression and serum PSA levels. The kava extract and flavokawain B effectively down-regulated the expression of both the full-length AR and AR splice variants. The kava extract and kavalactones accelerated AR protein degradation, while flavokawain B inhibited AR mRNA transcription via decreasing Sp1 expression and the binding of Sp1 to the AR promoter. The kava root extract and flavokawain B reduce tumor growth, AR expression in tumor tissues and levels of serum PSA in the patient-derived PCa xenograft models. These results suggest a potential usefulness of a safe kava product or its active components for prevention and treatment of advanced PCa by targeting AR.
authors.affiliation: Department of Urology, University of California Irvine, Orange, California, United States of America.
authors.forename: Xuesen
authors.initials: X
authors.lastname: Li
authors.forename: Zhongbo
authors.initials: Z
authors.lastname: Liu
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Blair
authors.forename: Zheng
authors.initials: Z
authors.lastname: Sun
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
authors.forename: Michael B
authors.initials: MB
authors.lastname: Lilly
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zi
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D020901:Kava; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D010946:Plants, Medicinal; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020033:Protein Isoforms; D011944:Receptors, Androgen / Q000235:genetics*; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects*
chemical_list: D020033:Protein Isoforms; D011944:Receptors, Androgen