Diclofenac, a selective COX-2 inhibitor, inhibits DMH-induced colon tumorigenesis through suppression of MCP-1, MIP-1α and VEGF.
Angiogenesis is a physiological process involving growth of new blood vessels from pre-existing ones; however, it also plays a critical role in tumor progression. It favors the transition from hyperplasia to neoplasia, that is, from a state of cellular multiplication to uncontrolled proliferation. Therefore targeting angiogenesis will be profitable as a mechanism to inhibit tumor's lifeline. Further, it is important to understand the cross-communication between vascular endothelial growth factor (VEGF)-master switch in angiogenesis and other molecules in the neoplastic and pro-inflammatory milieu. We studied the role of two important chemokines [monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-lα] alongwith VEGF and matrix metalloproteinases (MMPs) in non-steroidal anti-inflammatory drugs (NSAIDs)-induced chemopreventive effect in experimental colon cancer in rat. 1,2-Dimethylhydrazine (DMH, 30 mg/kg body weight, subcutaneously (s.c.) once-a-week) for 18 wk was used as pro-carcinogen and diclofenac (8 mg/kg body weight, orally daily) as the preferential cyclooxygenase-2 (COX-2) inhibitor. Expression of COX-2 and VEGF was found to be significantly elevated in the DMH-treated group as compared to the control, which was lowered notably by Diclofenac co-administration with DMH. Gelatin zymography showed prominent MMP-9 activity in the DMH-treated rats, while the activity was nearly absent in all the other groups. Expression of MCP-1 was found to be markedly increased whereas MIP-1α expression was found to be decreased in colonic mucosa from DMH-treated rats, which was reversed in the DMH + Diclofenac group. Our results indicate potential role of chemokines alongwith VEGF in angiogenesis in DMH-induced cancer and its chemoprevention with diclofenac.
Department of Biophysics, Panjab University, Chandigarh, India.
Jasmeet
J
Kaur
S N
SN
Sanyal
D019813:1,2-Dimethylhydrazine / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity*; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors*; D054405:Chemokine CCL3 / Q000037:antagonists & inhibitors*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D002273:Carcinogens; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D052246:Cyclooxygenase 2 Inhibitors; D042461:Vascular Endothelial Growth Factor A; D004008:Diclofenac; D019813:1,2-Dimethylhydrazine