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.
Highlights
Asian/Pacific men who consume a low fat and plant-based diet have the lowest rates of clinical prostate cancer (PCa) in the world [1,2]
The Cancer Council’s Cancer in New South Wales (NSW) Migrants 1991– 2001 report found [7] that the PCa incidence in Fijian men who migrated to and were resident in NSW, Australia, increased by 5.1 times compared to those living in Fiji
We report for the first time that a commercial kava extract and its active components downregulate androgen receptor (AR) expression
Summary
Asian/Pacific men who consume a low fat and plant-based diet have the lowest rates of clinical PCa in the world [1,2]. When Asian men migrate to the US, rates of clinical PCa increase [3] These observations implicate both environmental factors and dietary habits (such as consumption of low-fat and plant-based diet) in PCa development. Steiner [6] reported that the age-standardized cancer incidence for the three highest kava-drinking countries (Vanuatu, Fiji, and Western Samoa) was one fourth or one third that of non-kava-drinking countries, such as New Zealand and United States (Hawaii and Los Angeles), and non-kava-drinking Polynesians (Maoris). In these three kava-drinking countries more men drink kava and smoke than do women, yet there is a lower incidence of cancer for men than for women [6]. This report has prompted us to investigate the potential benefits of kava extracts and its active components for PCa prevention
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