Cisplatin and resveratrol induce apoptosis and autophagy following oxidative stress in malignant mesothelioma cells

• Cisplatin and resveratrol (CDDP/RSV) synergistically inhibits malignant mesothelioma (MM) cell proliferation.
• Oxidative mitochondrial damage is a mechanism responsible for MM cell toxicity induced by CDDP/RSV.
• ROS-dependent pathway is involved in CDDP/RSV-induced activation of both apoptosis and autophagy.
• Autophagy inhibition resensitizes H-2452 cells showing a low sensitivity to CDDP/RSV.
• Our data provide a rationale for targeting the autophagy regulation as a promising therapeutic strategy in MM.

Malignant mesothelioma (MM) is characterized by poor responsiveness to current chemotherapeutic drugs, usually owing to high resistance to apoptosis. Here, we investigated chemosensitizing effects of phytochemical resveratrol, in combination with cisplatin, on MM cells. The combination treatment of cisplatin and resveratrol (CDDP/RSV) synergistically induced apoptosis, as evidenced by typical cell morphological changes, the appearance of sub-G0/G1 peak, an increase in the Annexin V(+) cells and the cleavage of caspase-3 and PARP. CDDP/RSV increased ROS production and depolarization of mitochondrial membrane potential with an increase in the Bax/Bcl-2 ratio. These changes were attenuated by pretreatment with N-acetylcysteine, suggesting that CDDP/RSV induced apoptosis through oxidative mitochondrial damage. Compared with MSTO-211H cells, CDDP/RSV was less efficient in killing H-2452 cells. H-2452 cells exhibited an enhanced autophagy to CDDP/RSV, as observed by an increase in viable cells exhibiting intense LysoTracker Red staining and up-regulation of Beclin-1 and LC3A. Inhibition of autophagy by bafilomycin A1 rendered cells more sensitive to CDDP/RSV-induced cytotoxicity and this was associated with induction of apoptosis. These data indicate that the increased resistance of H-2452 cells to CDDP/RSV is closely related to the activation of self-defensive autophagy, and provide the rationale for targeting the autophagy regulation in the treatment of MM.

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