The SMAC Mimetic APG-1387 Sensitizes Immune-Mediated Cell Apoptosis in Hepatocellular Carcinoma.

Zide Chen,Jinlin Hou,Hongyan Liu,Wei Dong,Xiaoyong Zhang,Jiehua Chen,Dajun Yang,Xuan Huang

doi:10.3389/fphar.2018.01298

Abstract

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.

Highlights

Worldwide, hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality, with increasing incidence and poor prognosis (Ferlay et al, 2015)
Increased expression of cellular IAP1 (cIAP1) was present in 10/12 cases of HCC, increased expression of cellular IAP2 (cIAP2) was present in 9/12 cases of HCC, and increased expression of X chromosome-linked inhibitor of apoptosis protein (XIAP) was present in 9/12 cases of HCC (Figure 1A)
Immunohistochemistry analysis revealed that cIAP1 and cIAP2 were exclusively expressed in the cytoplasm of both tumor and non-tumor hepatocytes and were higher in tumor tissues than normal surrounding tissues (Supplementary Figure 1)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality, with increasing incidence and poor prognosis (Ferlay et al, 2015). In patients with intermediate- and advanced-stage HCC, only palliative treatments exist, and these include transarterial chemo-embolization, chemotherapy, and anti-angiogenic therapy, all of which have. There remains a need for the development of novel therapeutic strategies to improve the prognosis for patients diagnosed with HCC. Inhibitor of apoptosis proteins (IAPs), including cellular IAP1 (cIAP1), cellular IAP2 (cIAP2) and X chromosome-linked inhibitor of apoptosis protein (XIAP), are a family of anti-apoptotic proteins that block the caspases activation cascade (Fulda and Vucic, 2012). It has been known that IAPs are frequently abnormally upregulated in human malignancies, including HCC (Fulda and Vucic, 2012). IAPs might have potential as therapeutic targets in HCC therapy

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