Gen-27, a newly synthesized flavonoid, inhibits glycolysis and induces cell apoptosis via suppression of hexokinase II in human breast cancer cells

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• 作者：Lei Tao^a ; ¹ ; Libing Wei^b ; ¹ ; Yishi Liu^a ; Yang Ding^a ; Xiuting Liu^a ; Xin Zhang^a ; Xiaoping Wang^b ; Yuyuan Yao^b ; Jinrong Lu^c ; Qing Wang^d ; ^{wxwqnj@hotmail.com} ; Rong Hu^a ; ^{ronghu@cpu.edu.cn}
• 关键词：BCA ; bicinchoninic acid ; Cyt c ; cytochrome c ; DAPI ; 4&prime ; 6-diamidino-2-phenylindole ; DCFH/DA ; 2&prime ; 7&prime ; -dichlorodihydrofluorescein diacetate ; DMSO ; dimethylsulfoxide ; FBS ; Fetal bovine serum ; HKII ; hexokinase II ; LDHA ; lactate dehydrogenase ; MMP ; mitochondrial membrane potential ; MTT ; 3-(4 ; 5-dimethylthiazol-2-yl)-2 ; 5-diphenyltetrazolium bromide ; NAC ; N-acetylcysteine ; OXPHOS ; oxidative phosphorylation ; PARP ; poly (ADP-ribose) polymerase ; PBS ; phosphate buffered saline ; PFK ; 6-phospho
• 刊名：Biochemical Pharmacology
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：125
• 期：Complete
• 页码：12-25
• 全文大小：7823 K
• 卷排序：125

文摘

We have previously reported that Gen-27, a newly synthesized flavonoid, exhibits anticancer effects against human colorectal cancer cells. In this study, we investigated the anticancer effects in human breast cancer cell lines and its underlying mechanisms. We demonstrated that Gen-27 inhibited the growth and proliferation of human breast cancer cells in concentration and time-dependent manners. It was found that Gen-27 induced mitochondrial-mediated apoptosis, characterized by the dissipation of mitochondrial membrane potential (ΔΨm), cytochrome c (Cyt c) release from mitochondria to cytosol, activation of caspases and induction of poly (ADP-ribose) polymerase (PARP). In addition, Gen-27 inhibited the glycolysis in human breast cancer cells. After treatment with Gen-27, the expression of HKII was down-regulated, accompanied by weakened interaction of HKII and VDAC. Further research revealed that the induction of mitochondrial apoptosis was associated with the decrease of HKII expression by Gen-27. Finally, in vivo studies demonstrated that Gen-27 significantly suppressed the growth and promoted apoptosis of MDA-MB-231 breast cancer orthotopic tumors with low systemic toxicity. In conclusion, the results showed that Gen-27 had significant anticancer effects against human breast cancer and it may potentially be used as a novel anticancer agent for the treatment of breast cancer.