title: The insulin-like growth factor-I receptor inhibitor picropodophyllin-induced selective apoptosis of hepatocellular carcinoma cell through a caspase-dependent mitochondrial pathway.
abstract: The insulin-like growth factor-I receptor (IGF-1R) and its ligands (IGF-I, IGF-II) have been shown to be important promoters of cancer development and are frequently overexpressed in most hepatocellular carcinomas (HCCs). The activation of IGF-1R signaling mediates tumorigenesis, proliferation, and metastasis and thus represents a potential target for innovative treatment strategies for HCC. We investigated the potential inhibitory effect and mechanism of the impact of a novel IGF-1R inhibitor, picropodophyllin (PPP), in HCC lines. It was found that PPP selectively induced cell apoptosis in a time- and dose-dependent manner in HCC cells compared to normal hepatocytes. The inhibitory effects had a positive correlation with the expression of IGF-1R. PPP exerted an apoptotic effect in HCC cells in a caspase-dependent manner through the mitochondrial pathway. The release of cytochrome C from the mitochondrion was coupled with activation of caspase-9 and caspase-3. Treatment of PPP in HepG2 cells resulted in a marked elevation of Bax protein, but decreased levels of phosphorylated Akt and Bcl-2 protein. The ratio of Bax/Bcl-2 was increased in a dose-dependent manner. Our study provides strong evidence that the IGF-1R inhibitor PPP selectively inhibits the growth of human hepatocellular cancer cells by inducing the caspase-dependent mitochondrial pathway cell apoptosis pathway with no observed cytotoxicity on normal cells.
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, China-Japan Union hospital of Jilin University, Changchun, Jilin, China.
authors.forename: Changyong
authors.initials: C
authors.lastname: E
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Dan
authors.initials: D
authors.lastname: Shao
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.forename: Yue
authors.initials: Y
authors.lastname: Pan
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Xuewen
authors.initials: X
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008930:Mitochondria, Liver / Q000502:physiology; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: C494826:BAX protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C415032:picropodophyllin; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D011034:Podophyllotoxin