Abstract
Ponatinib is a multi-target protein tyrosine kinase inhibitor, and its effects on hepatocellular carcinoma cells have not been previously explored. In the present study, we investigated its effects on hepatocellular carcinoma cell growth and the underlying mechanisms. Toward SK-Hep-1 and SNU-423 cells, ponatinib induces apoptosis by upregulation of cleaved caspase-3 and -7 and promotes cell cycle arrest in the G1 phase by inhibiting CDK4/6/CyclinD1 complex and phosphorylation of retinoblastoma protein. It inhibits the growth-stimulating mitogen-activated protein (MAP) kinase pathway, the phosphorylation of Src on both negative and positive regulation sites, and Jak2 and Stat3 phosphorylation. Surprisingly, it also activates the PDK1, the protein kinase B (Akt), and the mechanistic target of rapamycin (mTOR) signaling pathway. Blocking mTOR signaling strongly sensitizes cells to inhibition by ponatinib and makes ponatinib a much more potent inhibitor of hepatocellular carcinoma cell proliferation. These findings demonstrate that ponatinib exerts both positive and negative effects on hepatocellular cell proliferation, and eliminating its growth-stimulating effects by drug combination or potentially by chemical medication can significantly improve its efficacy as an anti-cancer drug.
Highlights
Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality worldwide [1].Despite rapid progress in liver transplantation, resection, radiofrequency ablation, and chemoembolization, only one third of patients with HCC are suitable for these treatments [2]
Signaling strongly sensitizes cells to inhibition by ponatinib and makes ponatinib a much more potent inhibitor of hepatocellular carcinoma cell proliferation. These findings demonstrate that ponatinib exerts both positive and negative effects on hepatocellular cell proliferation, and eliminating its growth-stimulating effects by drug combination or potentially by chemical medication can significantly improve its efficacy as an anti-cancer drug
Drug intolerance and resistance to sorafenib restricted its use after several negative phase III clinical trials
Summary
Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality worldwide [1].Despite rapid progress in liver transplantation, resection, radiofrequency ablation, and chemoembolization, only one third of patients with HCC are suitable for these treatments [2]. Three small molecule kinase inhibitors, sorafenib, regorafenib, and lenvatinib, have been approved as targeted therapy for advanced stages of HCC for their effects in increasing survival and delaying tumor progression [4,5,6]. All these drugs work mainly as vascular endothelial growth factor receptor (VEGFR) inhibitors to block angiogenesis. Their use was restricted due to the drug resistance and intolerance. In the past few years, multiple clinical trials with drugs targeting the fibroblast growth factor receptor (FGFR), the VEGFR, the platelet-derived growth factor receptor (PDGFR), the epidermal growth factor receptor (EGFR), the insulin-like growth factor 1 receptor (IGF-1R), the mechanistic target of rapamycin (mTOR), and the Molecules 2019, 24, 1363; doi:10.3390/molecules24071363 www.mdpi.com/journal/molecules
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