The
inhibitor of apoptosis protein (IAP) genes are frequently overexpressed in
malignancies. Second mitochondria-derived activator of
caspase (SMAC) mimetics, which target IAPs, have potential to trigger
cancer cell death and sensitize
tumor cells to cytotoxic
therapy. The aim of this study was to investigate the anti-
tumor potential of a novel bivalent SMAC mimetic,
APG-1387, in
hepatocellular carcinoma (HCC). The
mRNA and
protein expressions of IAPs, including cellular IAPs (cIAP1 and cIAP2) and X chromosome-linked IAP (XIAP), were increased in HCC
tumors compared with normal liver tissue.
APG-1387 treatment alone significantly reduced the
protein levels of IAPs, but had only a modest effect on the viability and apoptosis of HCC cells in vitro. However,
APG-1387 in combination with
tumor necrosis factor-alpha (TNF-α) or
tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) significantly reduced cell viability and proliferation, and induced apoptosis in HepG2 cells, as well as in HCCLM3 cells that harbors cancer stem cell-like properties. These synergistic killing effects were
caspase-dependent and partially dependent on RIPK1
kinase activity. Furthermore,
APG-1387 also promoted the killing effect of Natural Killer cells on HCC cells in vitro and the combination
therapy significantly inhibited
tumor growth by inducing cell apoptosis in xenograft mice model. In conclusion, our study clarified that
APG-1387 could sensitize HCC cells to
cytokines or immune cells mediated cell killing and implied that potential of SMAC mimetic based combination
immunotherapy for HCC treatment.