title: FV-429 induces apoptosis and inhibits glycolysis by inhibiting Akt-mediated phosphorylation of hexokinase II in MDA-MB-231 cells.
abstract: In this study, the anticancer effect of a newly synthesized flavonoid FV-429, against human breast cancer MDA-MB-231 cells, and the underlying mechanisms were investigated. FV-429 triggered the apoptosis and simultaneously inhibited the glycolysis of MDA-MB-231 cells. Both the HK II activity and its level in mitochondria were significantly down regulated by FV-429. Moreover, FV-429 weakened the interaction between HKII and VDAC, stimulated the detachment of HK II from the mitochondria, and resulted in the opening of the mitochondrial permeability transition pores. Thus FV-429 induced the mitochondrial-mediated apoptosis, showing increased Bax/Bcl-2 ratio, loss of mitochondrial membrane potential (MMP) and activation of caspase-3 and -9, cytochrome c (Cyt c) release, and apoptosis inducing factor (AIF) transposition. Further research revealed that the phosphorylation of mitochondrial HKII via Akt was responsible for the dissociation of HKII and the decreased HKII activity induced by FV-429. Taken together, FV-429 inhibited the phosphorylation of HKII, down-regulated its activity, and stimulated the release of HKII from the mitochondria, resulting the inhibited glycolysis and mitochondrial-mediated apoptosis. The studies provide a molecular basis for the development of flavonoid compounds as novel anticancer agents for breast cancer. © 2015 Wiley Periodicals, Inc.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, JiangSu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, P. R. China.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, JiangSu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, P. R. China.
authors.forename: Na
authors.initials: N
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, JiangSu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, P. R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Qiao
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, JiangSu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, P. R. China.
authors.forename: Ting
authors.initials: T
authors.lastname: Ni
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, JiangSu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, P. R. China.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, 639# Long Mian Avenue, Nan Jing, P.R. China.
authors.forename: Boyang
authors.initials: B
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, JiangSu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, P. R. China.
authors.forename: Qinglong
authors.initials: Q
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, JiangSu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, P. R. China.
authors.forename: Libin
authors.initials: L
authors.lastname: Wei
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C569690:FV-429 compound; D005419:Flavonoids; D006593:Hexokinase; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; FV-429; HKII; breast cancer; mitochondrial-mediated apoptosis