title: Role of cytokines and Jak3/Stat3 signaling in the 1,2-dimethylhydrazine dihydrochloride-induced rat model of colon carcinogenesis: early target in the anticancer strategy.
abstract: The molecular mechanisms by which colon cancer cells regulate the expression of various proinflammatory and anti-inflammatory cytokines and transcription factors resulting in tumor progression have not been well clarified. The present study thus explores the effect of cancer cell-derived cytokines and transcription factors on the chemoprevention of a rat model of early colon carcinogenesis. Elevated expression of proinflammatory cytokines [interleukin-1β (IL-1β), IL-2, interferon γ, and tumor necrosis factor-α] and the transcription factors [Janus kinase 3 (Jak3) and signal transducer and activator of transcription 3 (Stat3)] was found in the 1,2-dimethylhydrazine dihydrochloride (DMH) group; however, this elevated expression was reversed by the individual and combination treatment with piroxicam, a traditional nonsteroidal anti-inflammatory drug [inhibiting both cyclooxygenase-1 (COX-1) and COX-2] and c-phycocyanin, a cyanobacterium-derived biliprotein from Spirulina platensis (selective COX-2 inhibitor). In the DMH group, low expression of IL-4, an anti-inflammatory cytokine, was further observed with respect to the other groups. Expression of inducible nitric oxide synthase and nitric oxide/citrulline levels was also analyzed and was found to be elevated with DMH treatment. Increased apoptotic index and stimulated levels of Bcl-2-associated death promoter (Bad), a proapoptotic protein, were observed in piroxicam-treated and c-phycocyanin-treated rats. In-silico molecular docking of piroxicam as a ligand with several regulatory proteins was performed, indicating that, except inducible nitric oxide synthase, it effectively binds with COX-1, COX-2, Jak3, and Stat3. Piroxicam and c-phycocyanin perhaps showed chemopreventive properties by inhibiting proinflammatory cytokines and Jak3/Stat3 signaling while promoting apoptosis. In addition, a combination regimen was found to be more beneficial than monotherapy.
authors.affiliation: Department of Biophysics, Panjab University, Chandigarh, India.
authors.forename: Manpreet Kaur
authors.initials: MK
authors.lastname: Saini
authors.forename: Vivek
authors.initials: V
authors.lastname: Vaish
authors.forename: Sankar Nath
authors.initials: SN
authors.lastname: Sanyal
mesh_terms: D019813:1,2-Dimethylhydrazine / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology*; D016503:Drug Delivery Systems / Q000379:methods; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D010894:Piroxicam / Q000008:administration & dosage; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; C507936:Jak3 protein, rat; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D010894:Piroxicam; D053616:Janus Kinase 3; D019813:1,2-Dimethylhydrazine