Chemopreventive effects of nonsteroidal anti-inflammatory drugs in the membrane lipid composition and fluidity parameters of the 1,2-dimethylhydrazine-induced colon carcinogenesis in rats.
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, celecoxib, and etoricoxib are reported to act as chemopreventive agents in experimental colon cancer induced by 1,2-dimethylhydrazine (DMH) as they are known cyclooxygenase (COX) enzyme inhibitors. To determine whether NSAIDs can also effectively modulate the membrane lipid compositions and the fluidity parameters of colonic brush border membrane, rats were injected subcutaneously (s.c.) with DMH 30 mg/kg body weight per week for 6 weeks. The animals were simultaneously treated with NSAIDs orally at the dose of aspirin, 60 mg/kg body weight; celecoxib, 6 mg/kg body weight; and etoricoxib, 0.6 mg/kg body weight. The animals were sacrificed after 6 weeks of treatments. Brush border membrane was isolated from proximal and distal portions of the colon. Membrane lipids were extracted and analyzed while the fluidity parameters were assessed by steady-state fluorescence polarization technique using the membrane extrinsic fluorophore 1,6-diphenyl-1,3,5-hexatriene (DPH). The translational diffusion was measured by using the excimer formation of pyrene incorporated in the membrane. Colonic mucosal changes in DMH alone and DMH+NSAID treated animals were assessed histologically. The results demonstrate that (a) there is a distinct occurrence of premalignant alterations in DMH-induced colon in the form of multiple plaque lesions (MPLs), which were greatly reduced by the NSAIDs used, (b) the membrane lipid changes in DMH-induced colon were completely restored back, (c) the alterations in membrane fluorescence polarization and the fluidity parameters are partially recovered, particularly with etoricoxib, and (d) the pyrene excimer formation process was completely restored. It may be concluded that the NSAIDs, particularly the coxib group of the drugs (COX-2 selective), are effective in chemoprevention in the DMH-induced colon carcinogenesis and membrane alterations.
Kanwar
Shailender Singh
SS
Department of Biophysics, Panjab University, Chandigarh, India.
Vaiphei
Kim
K
Nehru
Bimla
B
Sanyal
Sankar N
SN
D019813:1,2-Dimethylhydrazine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects*; D008563:Membrane Lipids / Q000378:metabolism*; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D002273:Carcinogens; D008563:Membrane Lipids; D019813:1,2-Dimethylhydrazine