title: A novel oxaliplatin derivative, Ht-2, triggers mitochondrion-dependent apoptosis in human colon cancer cells.
abstract: Ht-2 is a novel oxaliplatin derivative previously identified in a compound screen performed by our laboratory. In the present study, we evaluated the antitumor effects of Ht-2 and investigated its underlying mechanism of action. Ht-2 exhibited anti-tumor activity and demonstrated low cytotoxicity in normal cells in vitro. The IC50 of Ht-2 was 2-10-fold lower than oxaliplatin in all of the cancer cell lines tested except MCF-7 cells, whereas, the value was threefold higher than cisplatin or oxaliplatin in normal HUVEC cells. Further studies indicated that Ht-2 caused S-phase arrest and led to apoptosis in HCT-116 cells through the activation of the caspase cascade. Moreover, Ht-2 treatment contributed to increased mitochondrial permeability by altering the Bax/Bcl-2 ratio and consequently induced mitochondrial dysfunction, mitochondrial membrane potential depletion, reactive oxygen species (ROS) elevation and cytochrome C release in HCT-116 cells. The cellular antioxidative superoxide dismutase 1 protein was also downregulated. We demonstrated that the cytotoxicity was almost completely recovered by antioxidant treatment, indicating a crucial role of ROS for Ht-2-induced apoptosis. Collectively, our data suggest that Ht-2 can target tumor cells by inducing mitochondrion-dependent apoptosis.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Xing
authors.forename: Weiwei
authors.initials: W
authors.lastname: Bao
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Fan
authors.forename: Kunmei
authors.initials: K
authors.lastname: Liu
authors.forename: Xiaokang
authors.initials: X
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Xi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D000077150:Oxaliplatin; D017382:Reactive Oxygen Species / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C000600339:Ht-2 oxaliplatin compound; D009944:Organoplatinum Compounds; D017382:Reactive Oxygen Species; D000077150:Oxaliplatin