Abstract

16099 Background: Constitutive NF-κB activation is observed in prostate cancer and represents a predictor for biochemical recurrence after radical prostatectomy. Heightened activation of NF-κB is observed during the transition to androgen independence. Dietary agents such as pomegranate extract (PE) have received increasing attention as potential agents to prevent the onset or progression of many malignancies, including prostate cancer. We sought to determine whether extracts from the pomegranate fruit could inhibit NF-κB activation and growth of prostate cancer and delay the emergence of androgen independence in in vitro and in vivo models. Methods: The effects of PE on prostate cancer growth, proliferation, and apoptosis were assayed in vitro in multiple androgen- dependent and androgen-independent prostate cancer cell lines. NF-κB activity was measured by reporter gene and electrophoretic mobility shift assays. To evaluate the in vivo effects of PE, we also employed the LAPC4 xenograft model of androgen-independence. Tumor growth, proliferation and angiogenesis were measured. Results: PE inhibited NF-κB and cell viability in a dose- dependent fashion in vitro in DU145, LAPC4, CL1, and LNCaP-AR cell lines. In experiments in which NF-κB activity was maintained during PE exposure by transfecting NF-κB family member, we demonstrated that inhibition of NF-κB activation by PE is required for maximal apoptosis induced by PE. Moreover, in the LAPC4 xenograft model of androgen-independence, PE inhibited the heightened NF- κB activation that results from the emergence of androgen independence and reduced the growth of androgen-independent xenografts; this growth reduction was associated with an inhibition of proliferation and induction of apoptosis. Conclusions: PE extracts inhibit the growth of prostate cancer cells both in vitro and in vivo. Our study represents the first description of PE as a promising dietary agent for the prevention of the emergence of androgen independence through a mechanism that is at least in part driven by heightened NF-κB activity. No significant financial relationships to disclose.

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