Cyclooxygenase-independent induction of apoptosis by sulindac sulfone is mediated by polyamines in colon cancer.

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Babbar N, Ignatenko NA, Casero RA Jr, Gerner EW

Cyclooxygenase-independent induction of apoptosis by sulindac sulfone is mediated by polyamines in colon cancer.

J Biol Chem. 2003 Nov 28;278(48):47762-75. Epub 2003 Sep 23.

PubMed ID

14506281 [ View in PubMed

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Abstract

Sulindac, a non-steroidal anti-inflammatory prodrug, is metabolized into pharmacologically active sulfide and sulfone derivatives. Sulindac sulfide, but not sulindac sulfone, inhibits cyclooxygenase (COX) enzyme activities, yet both derivatives have growth inhibitory effects on colon cancer cells. Microarray analysis was used to detect COX-independent effects of sulindac on gene expression in human colorectal cells. Spermidine/sperm-ine N1-acetyltransferase (SSAT) gene, which encodes a polyamine catabolic enzyme, was induced by clinically relevant sulindac sulfone concentrations. Northern blots confirmed increased SSAT RNA levels in these colon cancer cells. Deletion analysis and mutational studies were done to map the sulindac sulfone-dependent response sequences in the SSAT 5'-flanking sequences. This led us to the identification of two peroxisome proliferator-activated receptor (PPAR) response elements (PPREs) in the SSAT gene. PPRE-2, at +48 bases relative to the transcription start site, is required for the induction of SSAT by sulindac sulfone and is specifically bound by PPAR gamma in the Caco-2 cells as shown by transfection and gel shift experiments. PPRE-1, at-323 bases relative to the start site, is not required for the induction of SSAT by sulindac sulfone but can be bound by both PPAR delta and PPAR gamma. Sulindac sulfone reduced cellular polyamine contents in the absence but not in the presence of verapamil, an inhibitor of the export of monoacetyl diamines, inhibited cell proliferation and induced apoptosis. The induced apoptosis could be partially rescued by exogenous putrescine. These data suggest that apoptosis induced by sulindac sulfone is mediated, in part, by the COX-independent, PPAR-dependent transcriptional activation of SSAT, leading to reduced tissue polyamine contents in human colon cancer cells.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Sulindac	Peroxisome proliferator-activated receptor delta	Protein	Humans	Unknown	Negative modulator	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Sulindac	Approved Investigational	SAT1	6303	upregulated	Sulindac results in increased expression of SAT1 mRNA	Xp22.11
Exisulind	Investigational	SAT1	6303	upregulated	sulindac sulfone results in increased expression of SAT1 mRNA	Xp22.11