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: Xuesen Li, Zhongbo Liu, Xia Xu, Christopher A Blair, Zheng Sun, Jun Xie, Michael B Lilly, Xiaolin Zi
• Journal: PloS one (PLoS One) Vol. 7 Issue 2 Pg. e31213 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22347450 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Protein Isoforms
• Receptors, Androgen

Topics

• Animals
• Cell Proliferation (drug effects)
• Down-Regulation (drug effects)
• Humans
• Kava
• Male
• Mice
• Neoplasm Transplantation
• Plants, Medicinal
• Prostatic Neoplasms (drug therapy, pathology)
• Protein Isoforms
• Receptors, Androgen (genetics)
• Transplantation, Heterologous
• Tumor Burden (drug effects)