Abstract 5421: Modulation of prostate cancer signaling and inhibition of tumor growth by a plant polyphenol butein

Abstract

Abstract Prostate cancer (PCa) is one of the most common cancers in men in the United States and is the second leading cause of male cancer death worldwide after lung cancer. Therefore, it is essential to find strategies for the prevention of PCa. Butein (3,4,2′,4′-tetrahydroxychalone), a plant polyphenol is one of the major biologically active components of the stem bark of cashews (Semecarpus anacardium), the heartwood of Dalbergia odorifera and the traditional Chinese and Tibetan medicinal herbs Caragana jubata and Rhus verniciflua Stokes. It has been traditionally used for treatment of pain, thrombotic disease, gastritis, stomach cancer and parasitic infections in Korea, Japan and China. In the present study, we determined the effect of butein on the inhibition of cell-growth, induction of apoptosis in human PCa cells in-vitro and on inhibition of tumor growth in athymic nude mice. Treatment with butein (10-30 µM; 48 h) caused decrease in the viability of LNCaP, CWR22Rν1 and PC-3 cells but had only minimal effect on normal prostate epithelial PrEC cells as assessed by the MTT assay. In butein-treated cells, there was also marked decrease in the protein expression of cyclins D1, D2 and E and their activating partners cdks 2, 4 and 6 with concomitant induction of WAF1/p21 and KIP1/p27. Treatment of cells with butein caused inhibition of (i) PI3K (p85 and p110), (ii) phosphorylation of Akt at both Ser473 and Thr308, (iii) NF-κB and IKKα, (iv) degradation and phosphorylation of IκBα, and (v) NF-κB DNA-binding activity. Butein treatment of cells also caused induction of apoptosis, PARP cleavage and modulation in the expressions of Bcl2-family proteins with significant activation of caspase-3, -8 and -9. Pretreatment of cells with caspase inhibitor (Z-VAD-FMK) blocked butein-induced activation of caspases. In athymic nude mice implanted with AR-positive CWR22Rν1 human PCa cells, treatment with butein resulted in significant inhibition of tumor growth. The appearance of small solid tumors was observed in animals of control group 7 days after cell inoculation. This latency period was prolonged to 14 days in animals receiving butein day 1 after tumor cell implantation. In control group, the average tumor volume of 1,200 mm3 was reached in 28 days after tumor cell inoculation. At this time point, the average tumor volume in butein treated group was 483 mm3. The average tumor volume of 1,200 mm3 in butein-treated group was achieved in 42 days after tumor cell inoculation. Quantitative sandwich ELISA was used to determine circulating PSA levels in mouse serum secreted by CWR22Rν1 tumor xenografts. At 28 days post-inoculation, there was 27% decrease in the secreted PSA levels in the butein-treated group as compared to the control group normalized to tumor volume. We suggest that butein could be developed as an agent against prostate cancer. 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 5421. doi:10.1158/1538-7445.AM2011-5421