title: III-10, a newly synthesized flavonoid, induces cell apoptosis with the involvement of reactive oxygen species-mitochondria pathway in human hepatocellular carcinoma cells.
abstract: Study of the mechanisms of apoptosis in tumor cells is an important field of tumor therapy and cancer molecular biology. We recently established that III-10, a new flavonoid with a pyrrolidinyl and a benzyl group substitution, exerted its anti-tumor effect via inducing differentiation of human U937 leukemia cells. In this study, we demonstrated that III-10 induced cell apoptosis in human hepatocellular carcinoma cells. The activation of caspase-3, caspase-9, and the increased expression ratio of Bax/Bcl-2 were detected in III-10-induced apoptosis. Z-VAD-FMK, a pan-caspase inhibitor, partly attenuated the apoptotic induction of III-10 on both HepG2 and BEL-7402 cells. Furthermore, the increase of intracellular reactive oxygen species levels and the reduction of mitochondria ΔΨm were also observed in BEL-7402 and HepG2 cells after the treatment of III-10. Pretreatment with NAC, a reactive oxygen species production inhibitor, partly attenuated the apoptosis induced by III-10 via blocking the reactive oxygen species generation. Our data also showed that III-10 induced the release of cytochrome c and AIF to cytosol followed after the reactive oxygen species accumulation. Moreover, the GSH levels and ATP generation were both inhibited after III-10 treatment. Besides, the MAPK, the downstream effect of reactive oxygen species accumulation including JNK could be activated by III-10, as well as the inactivation of ERK. Collectively, the generation of reactive oxygen species might play an crucial role in III-10-induced mitochondrial apoptosis pathway, provided more stubborn evidence for III-10 as a potent anticancer therapeutic candidate.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Qinsheng
authors.initials: Q
authors.lastname: Dai
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Yikai
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Xi'an Middle School of Shaanxi Province, Xi'an 710021, People's Republic of China.
authors.forename: Ruichen
authors.initials: R
authors.lastname: Guo
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
authors.forename: Shiping
authors.initials: S
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China. Electronic address: luna555@163.com.
authors.forename: Na
authors.initials: N
authors.lastname: Lu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D061945:Caspase Inhibitors / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D047309:Flavones / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D047309:Flavones; C574798:III-10; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione
keywords: Apoptosis; MAPK; MMP; Mitochondria; Reactive oxygen species