Abstract 4660: Antiproliferative effects of antagonists of Inhibitor of Apoptosis Proteins (IAPs) in human cancer cells

Abstract

Abstract The inhibitor of apoptosis (IAP) proteins are a family of proteins containing one or more conserved, cysteine and histidine-rich baculoviral IAP repeat (BIR) N-terminal domains and a C-terminal RING domain The BIR domains of the IAPs form the zinc-figure-like structures that bind to active caspases to block caspase activity. The RING domain acts as an ubiquitin ligase to facilitate proteasomal degradation of caspases. Upregulation of IAPs is found in many tumor cell lines as well as in most primary tumor tissues. Increased expression of IAPs has been associated with apoptosis resistance and low sensitivity to chemotherapy drugs in several tumor types. Recent studies have shown that inhibition of levels or functions of survivin and/XIAP with anti-sense, siRNA, and dominant negative mutant survivin genes induces the apoptotic cell death selectively in human tumor cells but not in normal cells. Like such, the importance of IAPs in regulating the apoptotic response and as molecular targets for production of therapeutic effects selectively in tumor cells have attracted a great attention to identify peptide antagonists or small molecule inhibitors for those proteins. In the effort to develop efficient antagonists of IAPs into chemotherapy drug, we analyzed the apoptotic effect of HM antagonists, novel small molecules inhibiting IAP activities, on non-small-cell lung cancer cells and colon cells. We also analyzed changes in cell signaling pathways after HM antagonists treatment to determine the mechanisms of the apoptotic response in cancer cells. Finally, the feasibility of using HM antagonists to sensitize human cancer cells to chemotherapy drugs was examined by combining HM antagonists with two commonly used agents, cisplatin and MK2206. In the present study, we have demonstrated that this reagent efficiently decreased IAPs expression in several NSCLC cells, especially on EGFR activated cells, as well as colon cells. It showed cleaved caspase 3 and PARP, and decreasing phosphor-Akt and phosphor-Erk, indicating that the reagents exerted antiapoptotic activity through inhibition of Akt and MAPK signaling pathways. Ongoing xenograft experiments using NSCLC cells and colon cells would manifest the potential chemotherapeutic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4660. doi:1538-7445.AM2012-4660