A Small Molecule Smac Mimic Potentiates TRAIL- and TNFα-Mediated Cell Death

Abstract

We describe the synthesis and properties of a small molecule mimic of Smac, a pro-apoptotic protein that functions by relieving inhibitor-of-apoptosis protein (IAP)-mediated suppression of caspase activity. The compound binds to X chromosome- encoded IAP (XIAP), cellular IAP 1 (cIAP-1), and cellular IAP 2 (cIAP-2) and synergizes with both tumor necrosis factor alpha (TNFalpha) and TNF-related apoptosis-inducing ligand (TRAIL) to potently induce caspase activation and apoptosis in human cancer cells. The molecule has allowed a temporal, unbiased evaluation of the roles that IAP proteins play during signaling from TRAIL and TNF receptors. The compound is also a lead structure for the development of IAP antagonists potentially useful as therapy for cancer and inflammatory diseases.

Mitochondria as therapeutic targets for cancer chemotherapy

“…Such Smac/ DIABLO peptidomimetics have been successfully used to induce apoptosis in vivo, in orthotopically implanted glioblastoma xenografts (Fulda et al, 2002). Moreover, small molecule Smac/DIABLO analogs have been developed and have been shown to sensitize to apoptosis induction several tumor cell lines (Li et al, 2004;Bockbrader et al, 2005), including MDA-MB-231 breast cancer cells characterized by high levels of IAPs (Bockbrader et al, 2005). …”

SMAC/Diablo mediates the proapoptotic function of PUMA by regulating PUMA-induced mitochondrial events

“…To test this possibility, we examined whether pharmacological agents that mimic the IAP inhibition function of SMAC have similar effects on PUMA-induced apoptosis. A small molecule mimics the AVPI amino-acid residues of SMAC that are responsible for IAP binding (C3) and a control compound (C4), which differs from C3 by a single methyl group, were used to treat the cells (Li et al, 2004). It was previously shown that C3, but not C4, at nanomolar concentrations can bind to IAPs and sensitize human cancer cells to TRAIL and TNF-ainduced apoptosis (Li et al, 2004).…”

“…SMAC/Diablo (hereafter referred to as SMAC) interacts with and antagonizes IAPs, such as XIAP, cIAP1 and cIAP2 (Verhagen et al, 2000). SMAC expression and agents that mimic the IAP interacting function of SMAC sensitize human cancer cells to apoptosis induced by several anticancer agents, such as tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) (Fulda et al, 2002;Arnt and Kaufmann, 2003;Li et al, 2004). Although substantial evidence suggests that SMAC plays an important role in execution of apoptosis, the precise function of SMAC remains obscure.…”

Revival of apoptotic cells that display early‐stage dynamic membrane blebbing

“…cFLIP, IAP, and Bcl-2 do not contribute to the revival of apoptotic cells and to the decrease of activated caspase 3 after 2DED2DD induction. Immunoblot analysis was performed using extracts of 2DED2DD-stably transfected cells 2,4,6,8,12,24, and 48 h after tetracycline induction. Extracts from cells cultured without tetracycline are also shown.…”

“…Malignant cells are able to survive because they counteract various apoptotic proteins through various means, including strong induction of anti-apoptotic proteins, amplification of anti-apoptotic genes, deletion of apoptotic genes, and depression of apoptotic proteins through epigenesis [1,2].…”