title: Cisplatin and resveratrol induce apoptosis and autophagy following oxidative stress in malignant mesothelioma cells.
abstract: 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.
authors: Department of Biochemistry, College of Medicine, Soonchunhyang University, Cheonan, 330-930, Republic of Korea; Division of Molecular Cancer Research, Soonchunhyang Medical Research Institute, Soonchunhyang University, Cheonan, 330-930, Republic of Korea.
authors: Yoon-Jin
authors: YJ
authors: Lee
authors: Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, MA, 02115-5000, USA.
authors: Gina J
authors: GJ
authors: Lee
authors: Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University, Asan, 336-745, Republic of Korea.
authors: Sun Shin
authors: SS
authors: Yi
authors: R&D Center, C.L. Pharm Co., Ltd., Seongdong-Gu, Seoul 04788, Republic of Korea.
authors: Su-Hak
authors: SH
authors: Heo
authors: Department of Biochemistry, College of Medicine, Soonchunhyang University, Cheonan, 330-930, Republic of Korea.
authors: Cho-Rong
authors: CR
authors: Park
authors: Division of Molecular Cancer Research, Soonchunhyang Medical Research Institute, Soonchunhyang University, Cheonan, 330-930, Republic of Korea.
authors: Hae-Seon
authors: HS
authors: Nam
authors: Division of Molecular Cancer Research, Soonchunhyang Medical Research Institute, Soonchunhyang University, Cheonan, 330-930, Republic of Korea.
authors: Moon-Kyun
authors: MK
authors: Cho
authors: Department of Biochemistry, College of Medicine, Soonchunhyang University, Cheonan, 330-930, Republic of Korea. Electronic address: m1037624@sch.ac.kr.
authors: Sang-Han
authors: SH
authors: Lee
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D018384:Oxidative Stress / Q000187:drug effects*; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
chemical_list: D013267:Stilbenes; D053148:Caspase 3; D002945:Cisplatin; D000077185:Resveratrol
keywords: Apoptosis; Autophagy; Chemoresistance; Cisplatin; Malignant mesothelioma; Resveratrol