SMAC mimetics sensitize nonsteroidal anti-inflammatory drug-induced apoptosis by promoting caspase-3-mediated cytochrome c release.
Nonsteroidal anti-inflammatory drugs (NSAID) are effective in suppressing the formation of colorectal tumors. However, the mechanisms underlying the antineoplastic effects of NSAIDs remain unclear. The effects of NSAIDs are incomplete, and resistance to NSAIDs is often developed. Growing evidence has indicated that the chemopreventive activity of NSAIDs is mediated by induction of apoptosis. Our previous studies showed that second mitochondria-derived activator of caspase (SMAC)/Diablo, a mitochondrial apoptogenic protein, plays an essential role in NSAID-induced apoptosis in colon cancer cells. In this study, we found that SMAC mediates NSAID-induced apoptosis through a feedback amplification mechanism involving interactions with inhibitor of apoptosis proteins, activation of caspase-3, and induction of cytosolic release of cytochrome c. Small-molecule SMAC mimetics at nanomolar concentrations significantly sensitize colon cancer cells to NSAID-induced apoptosis by promoting caspase-3 activation and cytochrome c release. Furthermore, SMAC mimetics overcome NSAID resistance in Bax-deficient or SMAC-deficient colon cancer cells by restoring caspase-3 activation and cytochrome c release. Together, these results suggest that SMAC is useful as a target for the development of more effective chemopreventive strategies and agents.
Bank
Alexander
A
Department of Pharmacology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Wang
Peng
P
Du
Chunying
C
Yu
Jian
J
Zhang
Lin
L
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D040761:Biomimetic Materials / Q000494:pharmacology* / Q000627:therapeutic use; D053148:Caspase 3 / Q000378:metabolism; D018890:Chemoprevention; D045304:Cytochromes c / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D024101:Mitochondrial Proteins / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000517:prevention & control*; D013467:Sulindac / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D051028:bcl-2-Associated X Protein; D013467:Sulindac; D045304:Cytochromes c; D053148:Caspase 3