期刊
MOLECULAR MEDICINE REPORTS
卷 16, 期 2, 页码 2133-2141出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/mmr.2017.6789
关键词
mesothelioma; sulforaphane; cisplatin; reactive oxygen species; apoptosis; autophagy
资金
- Basic Science Research Program through the National Research Foundation of Korea (NRF)
- Ministry of Education [NRF-2015R1D1A3A03020269]
- National Research Foundation of Korea [2015R1D1A3A03020269] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Sulforaphane (SFN) is an isothiocyanate compound derived from glucoraphanin, which is found in cruciferous vegetables, and has been heralded as a chemopreventive and/or chemotherapeutic agent. The present study investigated the effects of SFN on enhancing the anticancer role of cisplatin (cis-dichlorodiammineplatinum; CDDP) in H-28 malignant mesothelioma cells. At concentrations demonstrating limited toxicity in MeT-5A normal human mesothelial cells, combination treatment with the two compounds exhibited synergistic growth-inhibiting and apoptosis-promoting activities, as demonstrated by a series of proapoptotic events, including reactive oxygen species accumulation, loss of mitochondrial membrane potential, upregulation of p53 expression, increased B-cell lymphoma 2 (Bcl-2) associated X protein/Bcl-2 ratio, activation of caspase-3, the occurrence of a sub-G(0)/G(1) peak and an increase in cells with pyknotic and fragmented nuclei, Annexin V-phycoerythrin-positive staining and G(2)/M phase-transition delay in the cell cycle. The phosphorylation levels of Akt and mammalian target of rapamycin were reduced by the combination treatment, which was accompanied by a significant increase in the level of autophagosomal marker protein microtubule-associated protein 1 light chain 3B-II and the accumulation of acidic vesicular organelles. Pretreatment with the antioxidant N-acetylcysteine attenuated both apoptosis and autophagy, whereas inhibition of autophagy by bafilomycin A1 potentiated apoptotic cell death following the combination treatment with SFN and CDDP. Considering the pro-oxidant-based combinational approach, the results of the present study provide a rationale for targeting cytoprotective autophagy as a potential therapeutic strategy for malignant mesothelioma.
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