Abstract
BackgroundOvarian cancer remains a leading cause of death in women and development of new therapies is essential. Second mitochondria derived activator of caspase (SMAC) has been described to sensitize for apoptosis. We have explored the pro-apoptotic activity of LBW242, a mimic of SMAC/DIABLO, on ovarian cancer cell lines (A2780 cells and its chemoresistant derivative A2780/ADR, SKOV3 and HEY cells) and in primary ovarian cancer cells. The effects of LBW242 on ovarian cancer cell lines and primary ovarian cancer cells was determined by cell proliferation, apoptosis and biochemical assays.Principal FindingsLBW242 added alone elicited only a moderate pro-apoptotic effect; however, it strongly synergizes with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or anticancer drugs in inducing apoptosis of both ovarian cancer cell lines and primary ovarian cancer cells. Mechanistic studies show that LBW242-induced apoptosis in ovarian cancer cells is associated with activation of caspase-8. In line with this mechanism, c-FLIP overexpression inhibits LBW242-mediated apoptosis.ConclusionLBW242 sensitizes ovarian cancer cells to the antitumor effects of TRAIL and anticancer drugs commonly used in clinic. These observations suggest that the SMAC/DIABLO mimic LBW242 could be of value for the development of experimental strategies for treatment of ovarian cancer.
Highlights
Cancer is very complex multistep disorder involving the progressive accumulation of genetic and epigenetic abnormalities, which lead to the transformation of normal cells into malignant cells displaying the essential properties of cancer: resistance to apoptotic mechanisms, independency from growth signals, insensitivity to negative growth signals, invasive and metastatic capacities, unlimited replicative potential and sustained angiogenesis [1]
These observations suggest that the Second mitochondria derived activator of caspase (SMAC)/DIABLO mimic LBW242 could be of value for the development of experimental strategies for treatment of ovarian cancer
Three lines of evidence support a role for Inhibitor of Apoptosis (IAP) proteins in cancer: (i) elevated expression levels of IAP proteins, X-linked IAP (XIAP), c-IAP1 and c-IAP2, in a number of human cancer types correlate with tumor grade and prognosis [3]; (ii) a number of in vitro and in vivo studies have shown that downregulation of XIAP or c-IAP1 by various agents results in sensitization of cancer cells to chemotherapy- and gamma irradiation-induced apoptosis [4]; (iii) the chromosomal region 11q21-q23 containing c-IAP1 and cIAP2 genes is subject to chromosomal amplification in various tumors [3,4]
Summary
Cancer is very complex multistep disorder involving the progressive accumulation of genetic and epigenetic abnormalities, which lead to the transformation of normal cells into malignant cells displaying the essential properties of cancer: resistance to apoptotic mechanisms, independency from growth signals, insensitivity to negative growth signals, invasive and metastatic capacities, unlimited replicative potential and sustained angiogenesis [1]. The activity of IAPs is antagonized by SMAC/DIABLO (second-mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with low pI) that, after release from mitochondria in response to apoptotic triggering, undergoes maturation and cleavage of its N-terminal region, with consequent exposure of the AVPI sequence [8]. This tetrapepetide binds XIAP and competes with the same binding sites that are involved in the interaction with caspases [9]. The effects of LBW242 on ovarian cancer cell lines and primary ovarian cancer cells was determined by cell proliferation, apoptosis and biochemical assays
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