PPARgamma-mediated antineoplastic effect of NSAID sulindac on human oral squamous carcinoma cells.
There is strong evidence that nonsteroidal antiinflammatory drug (NSAID) sulindac may exert a significant antineoplastic effect. The purpose of our study was to explore the effects of sulindac on human oral squamous cell carcinoma (SCCa) cells and to elucidate the underlying molecular mechanisms. The changes that sulindac treatment induced on growth, apoptosis and cell cycle distribution of human oral SCCa cell lines were assessed by cell growth and flow cytometry experiments. Utilizing quantitative RT-PCR and immunocytochemistry, we determined the effect of sulindac treatment on mRNA and protein expression of different sulindac's targets. Also, PPARgamma expression was selectively targeted by antisense oligonucleotide treatment. Both sulfide and sulfone metabolites of sulindac, which differ in the ability to cause COX-2 inhibition, induced a significant dose- and time-dependent cell growth reduction accompanied by increase in apoptosis without concomitant cell cycle arrest. Sulindac treatment also caused upregulation of the protein and mRNA expression levels of COX-2 and PPARs. Treatment with antisense PPARgamma oligonucleotides abolished sulindac's growth inhibitory effect. Our results are consistent with a significant growth inhibitory effect of NSAID sulindac on human oral SCCa cells, which is mediated, at least partially, through induction of apoptosis. We suggest that upregulation of PPARgamma expression and activation may be, at least partially, responsible for sulindac's antiproliferative effect.
Nikitakis
Nikolaos G
NG
Department of Diagnostic Sciences and Pathology, University of Maryland, Baltimore, MD 21201-1586, USA. nin001@dental.umaryland.edu
Hebert
Carla
C
Lopes
Marcio A
MA
Reynolds
Mark A
MA
Sauk
John J
JJ
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D017931:DNA Primers; D007527:Isoenzymes; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D013467:Sulindac; C025462:sulindac sulfide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C025463:sulindac sulfone