Abstract
The present study aimed to determine whether grape seed extract (GSE) procyanidin mix, and its active constituent procyanidin B2 3,3″-di-O-gallate (B2G2) have the potential to target cancer stem cells (CSCs) in prostate cancer (PCa). The CSC populations were isolated and purified based on CD44+ -α2β1high surface markers in PCa cell lines LNCaP, C4-2B, 22Rv1, PC3, and DU145, and then subjected to prostasphere formation assays in the absence or presence of GSE or B2G2. Results indicated that at lower doses (<15 μg) , the GSE procyanidin mix produced activity in unsorted prostate cancer antigen (PCA) cells, but not in sorted; however, multiple treatments with low dose GSE over a course of time inhibited sphere formation by sorted PCA CSCs. Importantly, B2G2 demonstrated significant potential to target both unsorted and sorted CSCs at lower doses. As formation of spheroids, under specific in vitro conditions, is a measure of stemness, these results indicated the potential of both GSE and B2G2 to target the self-renewal of CSC in PCa cell lines, though B2G2 was more potent in its efficacy. Subsequent mechanistic studies revealed that both GSE procyanidins and B2G2 strongly decreased the constitutive as well as Jagged1 (Notch1 ligand)-induced activated Notch1 pathway. In totality, these in vitro studies warrant extensive dose-profiling-based assessments in vivo settings to conclusively determine the impact on CSC pool kinetics on the efficacy of both GSE and B2G2 to target PCa growth as well as tumor relapse.
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