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KMID : 1034820160120030289
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Molecular & Cellular Toxicology
2016 Volume.12 No. 3 p.289 ~ p.299
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Sulforaphane potentiates growth-inhibiting and apoptosis-promoting activities of cisplatin following oxidative stress and mitochondrial dysfunction in malignant mesothelioma cells
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Lee Yoon-Jin
Lee Sang-Han
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Abstract
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Functional defects in apoptosis signaling have been considered the important mechanism of chemoresistance in malignant mesothelioma (MM). This study was designed to explore the growth-inhibiting and apoptosis-promoting effects of sulforaphane and cisplatin on the human MM cell lines, MSTO-211H and H-2452, and examine the underlying mechanisms. Compared to normal mesothelial Met-5A cells, sulforaphane and cisplatin exhibited synergistic anti-cancer efficacy towards MM cells. By inducing ROS accumulation and mitochondrial dysfunction, sulforaphane potentiated cisplatin-induced cytotoxic effects, as evidenced by the increased nuclear fragmentation and chromatin condensation with the enhanced cleavage of procaspase-3 and PARP, the increased percentage of Annexin V-PE (+) cells, and the appearance of a sub-G0/G1 peak in the flow cytometric analysis. The apoptosis-inducing effects of two compounds were associated with the increased Bax/Bcl-2 ratio due to a decrease in the anti-apoptotic Bcl-2 level. A G2/M phase transition delay in the cell cycle following the combined treatment of sulforaphane and cisplatin was linked to the down-regulation of cyclin B1 and phospho-Cdc2 (Thr161) levels. In addition, the inhibition of ROS with N-acetylcysteine attenuated the apoptosis induced by the combination treatment, and recovered the depletion of mitochondrial membrane potential, revealing the vital role of ROS in the synergism. By targeting redox homeostasis, such a pro-oxidant-based combinational approach will help to enhance the therapeutic efficacy and preferential cytotoxicity on MM cells that conventional therapy would be ineffective.
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KEYWORD
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Sulforaphane, Cisplatin, Reactive oxygen species, Mitochondrial membrane potential, Apoptosis
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