title: Sulindac and Celecoxib regulate cell cycle progression by p53/p21 up regulation to induce apoptosis during initial stages of experimental colorectal cancer.
abstract: In the present study we have elaborated the putative mechanisms could be followed by the non-steroidal anti-inflammatory drugs (NSAIDs) viz. Sulindac and Celecoxib in the regulation of cell cycle checkpoints along with tumor suppressor proteins to achieve their chemopreventive effects in the initial stages of experimental colorectal cancer. Male Sprague-Dawley rats were administered with 1,2-dimethylhydrazine dihydrochloride (DMH) to produce early stages of colorectal carcinogenesis. The mRNA expression profiles of various target genes were analyzed by RT-PCR and validated by quantitative real-time PCR, whereas protein expression was analyzed by Western blotting. Nuclear localization of transcription factors or other nuclear proteins was analyzed by electrophoretic mobility shift assay and immunofluorescence. Flowcytometry was performed to analyze the differential apoptotic events and cell cycle regulation. Molecular docking studies with different target proteins were also performed to deduce the various putative mechanisms of action followed by Sulindac and Celecoxib. We observed that DMH administration has abruptly increased the proliferation of colonic cells which is macroscopically visible in the form of multiple plaque lesions and co-relates with the disturbed molecular mechanisms of cell cycle regulation. However, co-administration of NSAIDs has shown regulatory effects on cell cycle checkpoints via induction of various tumor suppressor proteins. We may conclude that Sulindac and Celecoxib could possibly follow p53/p21 mediated regulation of cell proliferation, where down regulation of NF-κB signaling and activation of PPARγ might serve as important additional events in vivo.
authors.affiliation: Department of Biophysics, Basic Medical Science Building, Panjab University, Chandigarh, 160014, India.
authors.forename: Vivek
authors.initials: V
authors.lastname: Vaish
authors.forename: Chandan
authors.initials: C
authors.lastname: Rana
authors.forename: Honit
authors.initials: H
authors.lastname: Piplani
authors.forename: Kim
authors.initials: K
authors.lastname: Vaiphei
authors.forename: Sankar Nath
authors.initials: SN
authors.lastname: Sanyal
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D000068579:Celecoxib; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism; D004334:Drug Administration Schedule; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013467:Sulindac / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D050759:Cyclin-Dependent Kinase Inhibitor p21; D008565:Membrane Proteins; D016328:NF-kappa B; D011720:Pyrazoles; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D013467:Sulindac; D051545:Cyclooxygenase 1; C496513:Ptgs1 protein, rat; D000068579:Celecoxib