Potent antileukemic interactions between flavopiridol and TRAIL/Apo2L involve flavopiridol-mediated XIAP downregulation

Abstract

Interactions between the cyclin-dependent kinase inhibitor flavopiridol (FP) and tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL/Apo2L), were examined in human leukemia cells (U937 and Jurkat). Coexposure of cells to marginally toxic concentrations of TRAIL and FP (24 h) synergistically increased mitochondrial injury (eg, cytochrome c, AIF, Smac/DIABLO release), cytoplasmic depletion of Bax, activation of Bid as well as caspase-8 and -3, PARP cleavage, and apoptosis. Coadministration of TRAIL markedly increased FP-induced apoptosis in leukemic cells ectopically expressing Bcl-2, Bcl-x L , or a phosphorylation loop-deleted form of Bcl-2 (DBcl-2), whereas lethality was substantially attenuated in cells ectopically expressing CrmA, dominant-negative-FADD, or dominant-negative-caspase-8. TRAIL/ FP induced no discernible changes in FLIP, DR4, DR5, Mcl-1, or survivin expression, modest declines in levels of DcR2 and c-IAP, but resulted in the marked transcriptional downregulation of XIAP. Moreover, cells stably expressing an XIAP-antisense construct exhibited a pronounced increase in TRAIL sensitivity comparable to degrees of apoptosis achieved with TRAIL/FP. Conversely, enforced XIAP expression significantly attenuated caspase activation and TRAIL/FP lethality. Together, these findings suggest that simultaneous activation of the intrinsic and extrinsic apoptotic pathways by TRAIL and FP synergistically induces apoptosis in human leukemia cells through a mechanism that involves FPmediated XIAP downregulation.

Roscovitine sensitizes breast cancer cells to TRAIL-induced apoptosis through a pleiotropic mechanism

“…We previously indicated that the formation of the DISC is a common target for different sensitizing regimes [24,49]. Indeed, CDK inhibitors have been reported to downregulate the expression of antiapoptotic proteins and to up-regulate the levels of pro-apoptotic regulatory proteins [24][25][26][27]50]. The apoptosis-inducing potential of the CDK inhibitor roscovitine led us to investigate its effects on the resistance of breast tumor cells to TRAIL.…”

“…While the mechanism by which CDK inhibitors induce apoptosis remains unclear, the CDK inhibitor flavopiridol, a semisynthetic flavone, reduces the levels of antiapoptotic proteins such as XIAP, Mcl-1 or cFLIP [24][25][26] and up-regulates the transcription factor E2F1, known to be involved in apoptosis [27]. Roscovitine may also downregulate Mcl-1 or XIAP [28] and it could sensitize glioma cells to TRAIL-induced apoptosis by reducing the levels of survivin and XIAP.…”

Constitutively Activated Nuclear Factor-κB, but not Induced NF-κB, Leads to TRAIL Resistance by Up-Regulation of X-Linked Inhibitor of Apoptosis Protein in Human Cancer Cells

“…Among these IAP members, XIAP seems to be the most potent direct caspase inhibitor (31,34) and has been shown to be overexpressed in tumor cells (36)(37)(38)(39). The implication of XIAP overexpression in resistance to TRAIL-mediated apoptosis was recently shown for different cancer cell lines (40)(41)(42)(43).…”

TRAIL sensitisation by arsenic trioxide is caspase-8 dependent and involves modulation of death receptor components and Akt

“…Strategies to overcome these mechanisms of resistance are the subject of intensive investigation. A variety of anticancer modalities including cytotoxic chemotherapy, radiation and novel therapies were shown to have additive or synergistic effects with TRAIL (Sayers et al, 2003;Ganten et al, 2004;Inoue et al, 2004;Rosato et al, 2004). However, in most of these studies, no mechanistic insight was provided.…”