Abstract 5572: An aqueous extract of allspice (Pimenta dioica) suppresses androgen receptor expression and prostate cancer growth

Abstract

Abstract Background and objective: The aromatic berries of the Jamaican plant Pimenta dioica called Allspice are used in many cuisines for their delectable flavor and as folk remedies for variety of ailments. Despite a rich source of antioxidants the use of Allspice as cancer preventive or anticancer agent has not been reported. Potential anti-cancer activity of an Aqueous Allspice extract (AAE) was tested on prostate cancer (CaP) cells and on tumor models. Methods: AAE was prepared from dried, unripe berries of P. dioica (Certified Organic, Oregon Spices, OR) in water and the extract was lyophilized before testing for biological activity. We tested AAE on growth, survival; response to androgen on human androgen sensitive (AR+) CaP cells (LNCaP, LAPC-4) and in LNCaP xenograft tumors in athymic-nude mice. We used colorimetric MTT-cell survival assay, colony-forming assays, bioluminescence reporter assays, Q-PCR and western blotting to delineate the molecular mechanism of tumor suppressive action of AAE. Results: AAE inhibited tumor cell proliferation (IC50∼100ug/ml) and clonogenic growth (IC50∼40ug/ml) of AR+ CaP cells. AAE was selectively toxic to tumor cells and less toxic to non-tumorigenic cells. AAE blocked cell cycle progression from G1 to S by decreasing cyclin D1, phosphorylated Rb, CDK4 and increased P21 and P27 in AR+ CaP cells. AAE induced apoptosis in LNCaP cells was mediated by intrinsic apoptotic pathway via depolarization of mitochondria, activation of caspase 9, caspase 3/7, cleaved PARP levels, increase in pro-apoptotic protein Bax, decrease in anti-apoptotic protein BID and release of cytochrome C from mitochondria. Importantly, AAE treated AR+ CaP cells showed significant decrease in AR protein level (IC50 50µg/ml) and the proteosome inhibitor MG132 did not rescue the AR protein level decrease by AAE. Transcriptional analysis of androgen receptor (AR) in AR+ CaP cells showed rapid decrease in AR and PSA expression by AAE. Moreover, treatment of LNCaP tumor bearing mice with AAE (100mg/kg, IP, 2x/w) significantly delayed the tumor growth (58%), prolonged the survival period with no systemic toxicity. Ex vivo analyses of LNCaP tumor tissue showed increased apoptosis (70%) in AAE treated mice compared to tissue from vehicle control, with 44% decrease in IGF-1 levels in serum of treated animals. A chemical analysis showed that the major component present on AAE was polyphenol (37% w/v) and devoid of alkaloids and other bioactive compounds. Conclusion: We identified an anticancer product from a New World plant commonly used in cuisines world-over. This extract suppressed the androgen receptor activity in AR+ CaP cells. These studies demonstrate potential use of AAE as a chemotherapeutic or chemopreventive agent against prostate cancer (Funds: NIH1R01 AT 003544 and VA MERIT Grant # 5312.01) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5572. doi:10.1158/1538-7445.AM2011-5572