Diclofenac, a selective COX-2 inhibitor, inhibits DMH-induced colon tumorigenesis through suppression of MCP-1, MIP-1α and VEGF

• Published in: Molecular carcinogenesis 2011-09, Vol.50 (9), p.707-718
• Main Authors: Kaur, Jasmeet, Sanyal, S.N.
• Format: Article
• Language: English
• Subjects: 1,2-Dimethylhydrazine - toxicity; 1,2‐dimethylhydrazine; 2-dimethylhydrazine; Animals; Blotting, Western; Carcinogens - toxicity; Chemokine CCL2 - antagonists & inhibitors; Chemokine CCL3 - antagonists & inhibitors; colon cancer; Colonic Neoplasms - chemically induced; Colonic Neoplasms - prevention & control; Cyclooxygenase 2 Inhibitors - pharmacology; Diclofenac - pharmacology; Immunohistochemistry; Male; MCP-1; MIP-1α; MMP-9; Rats; Vascular Endothelial Growth Factor A - antagonists & inhibitors; VEGF
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.20736

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. Mol. Carcinog. ©2011 Wiley‐Liss, Inc.