Pomegranate Extracts Potently Suppress Proliferation,Xenograft Growth,and Invasion of Human Prostate Cancer Cells

We completed a multicenter study of the effects of pomegranate cold-pressed (Oil) or supercritical CO₂-extracted(S) seed oil, fermented juice polyphenols (W), and pericarp polyphenols (P) on human prostate cancer cell xenograft growth in vivo, and/or proliferation, cell cycle distribution, apoptosis, gene expression, and invasion across Matrigel, in vitro. Oil, W, and P each acutely inhibited in vitro proliferation of LNCaP, PC-3, and DU 145 human cancer cell lines. The dose of P required to inhibit cell proliferation of the prostate cancer cell line LNCaP by 50% (ED₅₀) was 70 mg/mL, whereas normal prostate epithelial cells (hPrEC) were significantly less affected (ED50 5 250 mg/mL). These effects were mediated by changes in both cell cycle distribution and induction of apoptosis. For example, the androgen-independent cell line DU 145 showed a significant increase from 11% to 22% in G₂/M cells (P , .05) by treatment with Oil (35 µg/mL) with a modest induction of apoptosis. In other cell lines/treatments, the apoptotic response predominated, for example, in PC-3 cells treated with P, at least partially through a caspase 3-mediated pathway. These cellular effects coincided with rapid changes in mRNA levels of gene targets. Thus, 4-hour treatment of DU 145 cells with Oil (35 µg/mL) resulted in significant 2.3 ± 0.001-fold(mean ± SEM) up-regulation of the cyclin-dependent kinase inhibitor p21^(waf1/cip1) (P < .01) and 0.6 ± 0.14-fold down-regulation of c-myc (P < .05). In parallel, all agents potently suppressed PC-3 invasion through Matrigel, and furthermore P and S demonstrated potent inhibition of PC-3 xenograft growth in athymic mice. Overall, this study demonstrates significant antitumor activity of pomegranate-derived materials against human prostate cancer.