Abstract
BackgroundThe members of inhibitor of apoptosis proteins (IAPs) family are key negative regulators of apoptosis. Overexpression of IAPs are found in hepatocellular carcinoma (HCC), and can contribute to chemotherapy resistance and recurrence of HCC. Small-molecule Second mitochondria-derived activator of caspases (Smac) mimetics have recently emerged as novel anticancer drugs through targeting IAPs. The specific aims of this study were to 1) examine the anticancer activity of Smac mimetics as a single agent and in combination with chemotherapy in HCC cells, and 2) investigate the mechanism of anticancer action of Smac mimetics.MethodsFour HCC cell lines, including SMMC-7721, BEL-7402, HepG2 and Hep3B, and 12 primary HCC cells were used in this study. Smac mimetic SM-164 was used to treat HCC cells. Cell viability, cell death induction and clonal formation assays were used to evaluate the anticancer activity. Western blotting analysis and a pancaspase inhibitor were used to investigate the mechanisms.ResultsAlthough SM-164 induced complete cIAP-1 degradation, it displayed weak inhibitory effects on the viability of HCC cells. Nevertheless, SM-164 considerably potentiated Apo2 ligand or TNF-related apoptosis-inducing ligand (APO2L/TRAIL)- and Doxorubicin-mediated anticancer activity in HCC cells. Mechanistic studies demonstrated that SM-164 in combination with chemotherapeutic agents resulted in enhanced activation of caspases-9, -3 and cleavage of poly ADP-ribose polymerase (PARP), and also led to decreased AKT activation.ConclusionsSmac mimetics can enhance chemotherapeutic-mediated anticancer activity by enhancing apoptosis signaling and suppressing survival signaling in HCC cells. This study suggests Smac mimetics are potential therapeutic agents for HCC.
Highlights
Human hepatocellular carcinoma (HCC) is a common aggressive malignancy and the 5th leading cause of cancer death worldwide [1]
We found that SM-164 sensitizes HCC cells to APO2L/TRAIL, and greatly potentiates the cytotoxic effect of Doxorubicin, a standard chemotherapeutic drug on HCC cells
We first investigated the effect of Second mitochondriaderived activator of caspases (Smac) mimetic SM-164 on the levels of both Cellular IAP-1 (cIAP-1) and X-linked IAP (XIAP) in BEL-7402, SMMC-7721 HepG2 and Hep3B HCC cell lines with western blotting analysis
Summary
Human hepatocellular carcinoma (HCC) is a common aggressive malignancy and the 5th leading cause of cancer death worldwide [1]. A large majority of patients with advanced stage of HCC and compromised liver function depend on chemotherapy. HCC is inherently resistant to chemotherapeutic agents, leading to a dismal prognosis for HCC patients. It is imperative to explore novel drugs capable of overcoming chemotherapeutic resistance of HCC cells by removing these blockages. Overexpression of IAPs are found in hepatocellular carcinoma (HCC), and can contribute to chemotherapy resistance and recurrence of HCC. Small-molecule Second mitochondria-derived activator of caspases (Smac) mimetics have recently emerged as novel anticancer drugs through targeting IAPs. The specific aims of this study were to 1) examine the anticancer activity of Smac mimetics as a single agent and in combination with chemotherapy in HCC cells, and 2) investigate the mechanism of anticancer action of Smac mimetics
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