Gossypol Induces Apoptosis by Activating p53 in Prostate Cancer Cells and Prostate Tumor–Initiating Cells

Abstract

Prostate cancer continues to represent a burgeoning medical problem in the United States. Recent studies suggest that gossypol, a bioactive phytochemical produced by cotton plants, is a promising agent against prostate cancer. The current studies were undertaken to examine the chemotherapeutic efficacy of gossypol on human prostate cancer cell lines and prostate tumor-initiating cells. Gossypol reduced the viability of three prostate cancer cell lines (LAPC4, PC3, and DU145) with an IC 50 between 3 and 5 μmol/L. Additionally, gossypol was effective at inhibiting prostate tumor-initiating cell-driven tumor growth in a nonobese diabetic/severe combined immunodeficient xenograft model. Our integrated molecular profiling approach encompassing proteomics, activated transcription factors, and genomics suggests that the decrease in viability was associated with increased DNA damage and the induction of apoptosis. Exposure of DU145 cells to gossypol (1-10 μmol/L) resulted in the activation of 13 proteins and 7 transcription factors, and the expression of 17 genes involved in the mitochondrial pathway of apoptosis. These studies show for the first time that gossypol treatment induces DNA damage and activates p53. Collectively, these data support the use of gossypol as a novel agent for prostate cancer. Mol Cancer Ther; 9(2); 461-70. ©2010 AACR.

Breast cancer: Small molecules targeting apoptosis, a prospective approach to safe scientific success

“…Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces programmed cell death preferentially in tumour cells. TRAIL holds enormous promise as a cancer therapeutic due to its highly selective apoptosis-inducing action on neoplastic versus normal cells Moreover, a recently published Phase I clinical trial revealed that recombinant TRAIL administration is safe and well tolerated, and that dose escalation achieved peak TRAIL serum concentrations equivalent to those associated with preclinical antitumor efficacy [29]. However, to exploit the opportunity to successfully treat cancers with TRAIL, the problems of TRAIL resistance in a variety of tumor cells must first be overcome [30].…”

Cryptotanshinone targets tumor-initiating cells through down-regulation of stemness genes expression

“…The phytochemical sulphoraphane, derived from broccoli, can inhibit breast cancer TICs and down-regulate the Wnt/beta-catenin self-renewal pathway (26). Gossypol, a bioactive phytochemical produced by cotton plants, was effective at inhibiting prostate tumor-initiating cell-driven tumor growth in a NOD/SCID xenograft model (27).…”

Highlights of Natural Products in Prostate Cancer Drug Discovery

“…It also significantly enhances the antitumor activity of docetaxel in human PC both in vitro and in vivo. Gossypol effectively reduced the viability of LAPC4, PC-3, and DU145 PC cells and inhibited tumor growth in a NOD/SCID xenograft model (Volate et al, 2010). The growth of prostate tumor initiating cells (pTICs) isolated from DU145 (CD44+/hi) were also inhibited.…”

“…The growth of prostate tumor initiating cells (pTICs) isolated from DU145 (CD44+/hi) were also inhibited. The inhibitory effects of gossypol have been attributed to the induction of DNA damage, which consequently leads to the stabilization of p53 and the activation of the mitochondrial pathway of apoptosis (Volate et al, 2010). In addition, gossypol was recently reported to induce autophagy in human androgen-independent PC with a high level of Bcl-2 both in vitro and in vivo (Lian et al, 2011).…”