Cytoprotective effects of IAPs revealed by a small molecule antagonist

Abstract

SYNOPSIS Deregulated expression of members of the Inhibitor of Apoptosis (IAP) family has been found in a wide variety of neoplastic cells, and synthetic IAP antagonists represent a promising novel class of chemotherapeutic agents. Early work focused on the ability of these compounds to block the caspase inhibitory function of XIAP. However, recent studies have shown that IAP antagonists, although primarily designed to target XIAP, trigger a ubiquitin-mediated degradation of two related proteins, c-IAP1 and c-IAP2, and through this process potentiate the death of tumor cells via autocrine cellular signaling pathways. In this context, the relative contribution of XIAP as a target of this class of compounds is unclear. Here we examine the involvement of XIAP using a recently described synthetic IAP antagonist, AEG40730, and through the comparison of a human tumor cell line targeted for XIAP with its isogenic, wild type control line. Treatment with nanomolar concentrations of AEG40730 resulted in the loss of both XIAP and c-IAP1 proteins, albeit with different kinetics. While XIAP-deficient HCT116 cells retained some sensitivity to AEG40730 to external apoptotic stimuli, the data suggest that IAP antagonists such as AEG40730 exert their apoptotic enhancing effects through XIAP in addition to the c-IAPs. These data indicate that IAP antagonists can target multiple IAPs to augment distinct pro-apoptotic signaling pathways, thereby revealing the potential for these compounds in cancer therapy and underscoring the promise of IAP-targeted therapies.

Fas death receptor signalling: roles of Bid and XIAP

“…Accordingly, there is increasing experimental evidence that small molecule IAP antagonists can sensitise resistant cancer cells towards TRAIL and/or TNF-induced killing, either given as single agents, or in combination with classical chemotherapeutic drugs (Figure 3). [112][113][114][115][116] The IAP antagonists available today target multiple members of the IAP family, including cIAP1, cIAP2 and XIAP (see Table 1 for an overview of current clinical trials using IAP antagonists). 117 Given the role of cIAP1 and cIAP2 in the regulation of proximal events in TNF-R1 signalling, 117,118 antagonists that are highly specific for XIAP may be even better suited than broad spectrum IAP inhibitors for cancer therapy.…”

Drug resistance in mutant FLT3-positive AML

“…Recent study has indicated that IAP inhibitors can target multiple IAPs (that is, XIAP, c-IAP) to enhance the activity of different proapoptotic signaling pathways (Galban et al, 2009). However, the role of XIAP in intrinsic versus extrinsic death pathways is unclear; recent studies suggest that it has a more significant role in regulating death receptor-mediated apoptosis than intrinsic pathway-mediated cell death (Sensintaffar et al, 2010).…”

Distinctive effects of the cellular inhibitor of apoptosis protein c-IAP2 through stabilization by XIAP in glioblastoma multiforme cells

“…10 This result suggests that XIAP is required to protect nascent c-IAP2 from degradation. To confirm this hypothesis, XIAP-null HCT116 18 and MEF cells 19 were treated with TNFα, and then c-IAP2 levels were measured. The 2 h TNF=induced upregulation of c-IAP2 was attenuated in XIAP-null HCT116 cells (Fig.…”

“…MEF cells with wild-type or knocked-out XIAP were transformed with v-Ras/v-E1A, and HCT116 cells with wild-type or null XIAP were cultured as described previously. 18,19 TNFα (8902) was purchased from Cell Signaling.…”