Sulindac sulfide-induced apoptosis is enhanced by a small-molecule Bcl-2 inhibitor and by TRAIL in human colon cancer cells overexpressing Bcl-2.

Abstract

Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) that induces apoptosis in cultured colon cancer cells and in intestinal epithelia in association with its chemopreventive efficacy. Resistance to sulindac is well documented in patients with familial adenomatous polyposis; however, the molecular mechanisms underlying such resistance remain unknown. We determined the effect of ectopic Bcl-2 expression upon sulindac-induced apoptotic signaling in SW480 human colon cancer cells. Sulindac sulfide activated both the caspase-8-dependent and mitochondrial apoptotic pathways. Ectopic Bcl-2 attenuated cytochrome c release and apoptosis induction compared with SW480/neo cells. Coadministration of sulindac sulfide and the small-molecule Bcl-2 inhibitor HA14-1 increased apoptosis induction and enhanced caspase-8 and caspase-9 cleavage, Bax redistribution, and cytochrome c and second mitochondria-derived activator of caspase release. Given that sulindac sulfide activated caspase-8 and increased membrane death receptor (DR4 and DR5) protein levels, we evaluated its combination with the endogenous death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Coadministration of sulindac sulfide and TRAIL cooperatively enhanced apoptotic signaling as effectively as did HA14-1. Together, these data indicate that HA14-1 or TRAIL can enhance sulindac sulfide-induced apoptosis and represent novel strategies for circumventing Bcl-2-mediated apoptosis resistance in human colon cancer cells.

• Authors: Frank A Sinicrope, Robert C Penington
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 4 Issue 10 Pg. 1475-83 (Oct 2005) ISSN: 1535-7163 [Print] United States
• PMID: 16227396 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Apoptosis Regulatory Proteins
• Benzopyrans
• Enzyme Inhibitors
• Membrane Glycoproteins
• Nitriles
• Proto-Oncogene Proteins c-bcl-2
• Receptors, Tumor Necrosis Factor
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Tumor Necrosis Factor-alpha
• ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate
• Sulindac
• sulindac sulfide
• Cytochromes c
• CASP8 protein, human
• CASP9 protein, human
• Caspase 8
• Caspase 9
• Caspases

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects, physiology)
• Apoptosis Regulatory Proteins (pharmacology)
• Benzopyrans (pharmacology)
• Caspase 8
• Caspase 9
• Caspases (metabolism)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cytochromes c (metabolism)
• Drug Resistance, Neoplasm
• Drug Synergism
• Enzyme Inhibitors (pharmacology)
• Humans
• Membrane Glycoproteins (pharmacology)
• Mitochondria (drug effects, physiology)
• Nitriles (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, biosynthesis, genetics)
• Receptors, Tumor Necrosis Factor (biosynthesis)
• Sulindac (analogs & derivatives, pharmacology)
• TNF-Related Apoptosis-Inducing Ligand
• Transfection
• Tumor Necrosis Factor-alpha (pharmacology)