Gossypol is a BH3-mimetic small-molecule pan-inhibitor of Bcl-2. In this study, we described the potential therapeutic effects of gossypol on BRAF inhibitor-resistant melanoma cells. We found that gossypol retained its efficacy in mutant melanoma clones resistant to BRAF inhibitor through a mechanism independent of MEK-ERK inhibition. Gossypol caused G2/M arrest in BRAF mutant A375P cells with high expression of p21Cip1, regardless of their drug resistance. Interestingly, we determined that the lack of gossypol-induced mitotic arrest in BRAF-WT-harboring SK-MEL-2 cells was associated with a low level of p21Cip1 expression. In addition, gossypol preferentially induced autophagy and apoptosis in the gossypol-sensitive cells and not in the gossypol-resistant SK-MEL-2 cells, which suggests that apoptosis and autophagy can occur simultaneously and act as cooperative partners for the induction of cell death. Taken together, these results suggest that gossypol may exhibit potential for the treatment of BRAF inhibitor-resistant tumors, but a functional p21Cip1 is a prerequisite for a positive response to its clinical application.
Citation Format: Michael Lee, Gun-Hee Jang, Jun-Ho Ahn, Na-Yeon Kim. BH3-mimetic gossypol promotes autophagy to inhibit the proliferation of mutant BRAF melanoma cells with high expression of p21Cip1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1337. doi:10.1158/1538-7445.AM2014-1337