title: Small molecular anticancer agent SKLB703 induces apoptosis in human hepatocellular carcinoma cells via the mitochondrial apoptotic pathway invitro and inhibits tumor growth invivo.
abstract: Inducing apoptosis is a promising therapeutic approach to overcome cancer. Here we described that a novel synthesized compound, 3-amino-N-(4-chlorobenzyl)-6-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide (SKLB703), exhibits antitumor activity via inducing apoptosis both invitro and invivo. Our results showed that SKLB703 inhibited the proliferation of a panel of human cancer cell lines, and human hepatocellular carcinoma cell line HepG2 was the most sensitive. The proliferation inhibitory effect of SKLB703 was associated with its apoptosis-inducing effect by activating caspase-3 and caspase-9 rather than caspase 8. Exposure of HepG2 to SKLB703 also resulted in Bax upregulation, Bcl-2 downregulation, cytochrome c release and mitochondrial transmembrane potential change in mitochondrial apoptotic pathway. Moreover, the decrease of phosphorylated p 44/42 mitogen-activated protein kinase and phosphorylated Akt was observed. SKLB703 suppressed the growth of established tumors in xenograft models in mice, whereas no toxicity was exhibited. TUNAL analysis showed that SKLB703 induced HepG2 tumor apoptosis. Taken together, the present study demonstrates that SKLB730 exhibits its antitumor activity through inducing apoptosis via mitochondrial apoptotic pathway. Its potential to be a candidate of anticancer agent is worth being further investigated.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: You-Zhi
authors.initials: YZ
authors.lastname: Xu
authors.forename: Ren-Lin
authors.initials: RL
authors.lastname: Zheng
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Feng
authors.initials: F
authors.lastname: Peng
authors.forename: Hong-Jun
authors.initials: HJ
authors.lastname: Lin
authors.forename: Qian
authors.initials: Q
authors.lastname: Bu
authors.forename: Yong-Qiu
authors.initials: YQ
authors.lastname: Mao
authors.forename: Luo-Ting
authors.initials: LT
authors.lastname: Yu
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
authors.forename: Ying-Lan
authors.initials: YL
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D020014:K562 Cells; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C569116:3-amino-N-(4-chlorobenzyl)-6-(3-methoxyphenyl)thieno(2,3-b)pyridine-2-carboxamide; D000970:Antineoplastic Agents; D011725:Pyridines; D013876:Thiophenes; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases