The insulin-like growth factor-I receptor inhibitor picropodophyllin-induced selective apoptosis of hepatocellular carcinoma cell through a caspase-dependent mitochondrial pathway

Changyong E, Jing Li, Dan Shao, Dan Zhang, Yue Pan, Li Chen, Xuewen Zhang
Oncology Research 2013, 21 (2): 103-10
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.

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