Drug resistance to current chemotherapy regimens has been considered a cell survival adaptive response in malignant mesothelioma cells. Therefore, new strategies to enhance the apoptotic signal and overcome resistance to chemotherapeutics are necessary to improve treatment outcomes for this deadly disease. Here, the effect of sulforaphane, an isothiocyanate compound derived from glucoraphanin present in cruciferous vegetables, on enhancing anticancer role of cisplatin was investigated in malignant mesothelioma cells. At concentrations showing little toxicity in normal human mesothelial MeT-5A cells, the combined treatment with both compounds exhibited synergistic growth-inhibiting and apoptosis-promoting effects, as demonstrated in a series of pro-apoptotic events including reactive oxygen species (ROS) accumulation, loss of mitochondrial membrane potential, up-regulation of p53, increased Bax/Bcl-2 ratio, activation of caspase-3, and the occurrence of a sub-G0/G1 peak with an increase in the cells with pyknotic and fragmented nuclei, Annexin V-PE(+), and G2/M phase transition delay in the cell cycle. The levels of phosphorylation of both Akt and mTOR were decreased by the combined treatment, which was accompanied by a significant increase in the level of autophagosomal marker protein LC3-II and the accumulation of acidic vesicular organelles. Furthermore, scavenging of ROS by antioxidant N-acetylcysteine inhibited both the apoptosis and autophagy, while the inhibition of autophagy by bafilomycin A1 potentiated apoptotic cell death following the combination treatment of sulforaphane and cisplatin, indicating the cytoprotective role of autophagy counteracts apoptosis of malignant mesothelioma cells. Considering the pro-oxidant-based combinational approach, our data provide a rationale for targeting cytoprotective autophagy as a potential therapeutic strategy for malignant mesothelioma.
Citation Format: Yoon Jin Lee, David M. Lee, Hae Nam, Sang Lee. Inhibition of autophagy enhances mitochondria-mediated apoptosis in malignant mesothelioma cells by cisplatin and sulforaphane [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3304. doi:10.1158/1538-7445.AM2017-3304