lbw242 and Ovarian-Neoplasms

Ovarian 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.. LBW242 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.. LBW242 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.

Topics: Analysis of Variance; Annexin A5; Antineoplastic Agents; Blotting, Western; Cell Death; Cell Line, Tumor; Drug Synergism; Female; Flow Cytometry; Humans; In Vitro Techniques; Oligopeptides; Ovarian Neoplasms; TNF-Related Apoptosis-Inducing Ligand; Topotecan; Transduction, Genetic

Smac mimetic compounds targeting the inhibitor of apoptosis proteins (IAP) baculoviral IAP repeat-3 domain are presumed to reduce the threshold for apoptotic cell death by alleviating caspase-9 repression. We explored this tenet in an unbiased manner by searching for small interfering RNAs that are able to confer resistance to the Smac mimetic compound LBW242. Among the screening hits were multiple components of the tumor necrosis factor alpha (TNFalpha) signaling pathway as well as X-linked inhibitor of apoptosis (XIAP) itself. Here, we show that in a subset of highly sensitive tumor cell lines, activity of LBW242 is dependent on TNFalpha signaling. Mechanistic studies indicate that in this context, XIAP is a positive modulator of TNFalpha induction whereas cellular inhibitor of apoptosis protein 1 negatively regulates TNFalpha-mediated apoptosis.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Cell Death; Cell Line, Tumor; Conserved Sequence; Female; Humans; Inhibitor of Apoptosis Proteins; Intracellular Signaling Peptides and Proteins; Mitochondrial Proteins; Oligopeptides; Ovarian Neoplasms; RNA Interference; RNA, Neoplasm; RNA, Small Interfering; Signal Transduction; Tumor Necrosis Factor-alpha; X-Linked Inhibitor of Apoptosis Protein