Failure of autophagy induction makes multidrug resistant cells vulnerable to BH3‐mimetic gossypol

Abstract

Developing potential therapeutic strategies to overcome multidrug resistance (MDR) is a major challenge in cancer research. Here, we explored the use of gossypol as a chemotherapeutic agent that is effective against both v‐Ha‐ras‐transformed NIH 3T3 cells (Ras‐NIH 3T3) and their mdr equivalents (Ras‐NIH 3T3/Mdr). We found that Ras‐NIH 3T3/Mdr cells, which exhibit a strong cross‐resistance to many chemotherapeutic agents, exhibited essentially no resistance to gossypol. This study also revealed that gossypol significantly decreased mdr‐1 and mdr‐3 mRNA expression in Ras‐NIH 3T3/Mdr cells. However, the rhodamine assay indicated that P‐glycoprotein is not likely to be a major mechanism of the chemotherapy sensitization by gossypol. While both cell lines can be growth arrested, cell death is apoptotic in the Ras‐NIH 3T3 cells but mixed necrotic and apoptotic in the Ras‐NIH 3T3/Mdr cells. More notably, gossypol preferentially induced autophagy in Ras‐NIH 3T3 cells but not in Ras‐NIH 3T3/Mdr cells, suggesting that defective autophagy makes MDR cells vulnerable to gossypol despite being resistant to G2/M block. Taken together, these results suggest that gossypol could be an effective anticancer agent to treat malignancies that are resistant to conventional therapies, either used alone or in association with other autophagy‐blocking treatments.