Diclofenac, a selective COX-2 inhibitor, inhibits DMH-induced colon tumorigenesis through suppression of MCP-1, MIP-1α and VEGF
Jasmeet Kaur
Department of Biophysics, Panjab University, Chandigarh, India
Search for more papers by this authorCorresponding Author
S.N. Sanyal
Department of Biophysics, Panjab University, Chandigarh, India
Department of Biophysics, Panjab University, Chandigarh 160 014, India.Search for more papers by this authorJasmeet Kaur
Department of Biophysics, Panjab University, Chandigarh, India
Search for more papers by this authorCorresponding Author
S.N. Sanyal
Department of Biophysics, Panjab University, Chandigarh, India
Department of Biophysics, Panjab University, Chandigarh 160 014, India.Search for more papers by this authorAbstract
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.
REFERENCES
- 1 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1: 27–31.
- 2 Mitchell RN, Cotran RS. Hemodynamic disorders, thrombosis, and shock. In: RS Cotran, editor. Pathologic basis of disease. 6th edition. Philadelphia: WB Saunders Co; 1999. pp. 113–138.
- 3 Cotran RS, Kumar V, Collins T. Acute and chronic inflammation. In: RS Cotran, editor. Pathologic basis of disease. 6th edition. Philadelphia: WB Saunders Co.; 1999. pp. 50–88.
- 4 Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990; 82: 4–6.
- 5 Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med 1971; 285: 1182–1186.
- 6 Gimbrone M, Leapman S, Cotrans R, Folkman J. Tumor dormancy in vitro by prevention of neovascularization. J Exp Med 1972; 136: 261–276.
- 7 O'Connor DS, Schechner JS, Adida C, et al. Control of apoptosis during angiogenesis by survivin expression in endothelial cells. Am J Pathol 2000; 156: 393–398.
- 8 Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: Role of the HIF system. Nat Med 2003; 9: 677–684.
- 9 Hendrix MJ, Seftor EA, Hess AR, Seftor RE. Vasculogenic mimicry and tumor-cell plasticity: Lessons from melanoma. Nat Rev Cancer 2003; 3: 411–421.
- 10 Bernardini G, Ribatti D, Spinetti G, et al. Analysis of the role of chemokines in angiogenesis. J Immunol Methods 2002; 273: 83–101.
- 11 Rollins BJ. Chemokines. Blood 1997; 90: 909–928.
- 12 Brown KD, Zurawski SM, Mossmann TR, Zurwski C. A family of small inducible proteins secreted by leukocytes is members of a new superfamily that include leukocyte and fibroblast-derived inflammatory agents, growth factors and indicators of various activation processes. J Immunol 1989; 142: 679–687.
- 13 Ohta M, Kitadai Y, Tanaka S, et al. Monocyte chemoattractant protein-1 expression correlates with macrophage infiltration and tumor vascularity in human gastric carcinomas. Int J Oncol 2003; 22: 773–778.
- 14 Timmers HT, Pronk GJ, Bos JL, van-der-Eb AJ. Analysis of the rat JE gene promoter identifies an AP-1 binding site essential for basal expression but not for TPA induction. Nucleic Acids Res 1990; 18: 23–34.
- 15 Oppenheim JJ, Zachariae CO, Mukaida N, Matsushima K. Properties of the novel pro-inflammatory supergene ‘intercrine’ cytokine family. Annu Rev Immunol 1991; 9: 617–648.
- 16 Koide N, Nishio A, Sato T, Sugiyama A, Miyagawa S. Significance of macrophage chemoattractant protein-1 expression and macrophage infiltration in squamous cell carcinoma of the esophagus. Am J Gastroenterol 2004; 99: 1667–1674.
- 17 Cheadle EJ, Riyad K, Subar D, et al. Eotaxin-2 and colorectal cancer: A potential target for immune therapy. Clin Cancer Res 2007; 13: 5719–5728.
- 18 Kaur J, Sanyal SN. PI3-kinase/Wnt signaling association mediates COX-2/PGE2 pathway to inhibit apoptosis in early stages of colon carcinogenesis and its chemoprevention by diclofenac. Tumor Biol 2010; 31: 623–631.
- 19 Kaur J, Sanyal SN. Modulation of inflammatory changes in early stages of colon cancer through activation of PPARγ by diclofenac. Eur J Cancer Prev 2010; 19: 319–327.
- 20 Kaur J, Sanyal SN. Intrinsic mitochondrial membrane potential change and associated events mediate apoptosis in chemopreventive effect of diclofenac in colon cancer. Oncol Res 2010; 18: 481–492.
- 21 Kaur J, Sanyal SN. Alterations in membrane fluidity and dynamics during initial stages of colon carcinogenesis and its chemoprevention by diclofenac. Mol Cell Biochem 2010; 341: 99–108.
- 22 Kaur J, Sanyal SN. Induction of apoptosis as potential chemopreventive effect of dual cyclooxygenase inhibitor, diclofenac in early colon carcinogenesis. J Environ Pathol Toxicol Oncol 2010; 29: 41–53.
- 23 Kaur J, Sanyal SN. Oxidative stress and stress-signaling in chemoprevention of early colon cancer by diclofenac. Am J Biomed Sci 2010; 2: 63–78.
- 24 Kaur J, Sanyal SN. Association of PI3-kinase and Wnt signaling in non-steroidal anti-inflammatory drug-induced apoptosis in experimental colon cancer. Am J Biomed Sci 2009; 1: 395–405.
- 25 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248–254.
- 26 Billings PC, Habres JM, Liao DC, Tuttle SW. Human fibroblasts contain a proteolytic activity which is inhibited by the Bowman–Birk protease inhibitor. Cancer Res 1991; 51: 5539–5543.
- 27 Brittan M, Wright NA. Stem cell in gastrointestinal structure and neoplastic development. Gut 2004; 53: 899–910.
- 28 van Leeuwen IMM, Edwards CM, Ilyas M, Byrne HM. Towards a multiscale model of colorectal cancer. World J Gastroenterol 2007; 13: 1399–1407.
- 29 Sengottuvelan M, Senthilkumar R, Nalini N. Modulatory influence of dietary resveratrol during different phases of 1,2-dimethylhydrazine induced mucosal lipid-peroxidation, antioxidant status and aberrant crypt foci development in rat colon carcinogenesis. Biochim Biophys Acta 2006; 1760: 1175–1183.
- 30 Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells over-expressing prostaglandin endoperoxide synthase 2. Cell 1995; 83: 493–501.
- 31 Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998; 93: 705–716.
- 32 Janakiram NB, Rao CV. Role of lipoxins and resolvins as anti-inflammatory and proresolving mediators in colon cancer. Curr Mol Med 2009; 9: 565–579.
- 33 Hanahan D, Folkman J. Patterns and emerging mechanism of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353–364.
- 34 Furuya M, Nishiyama M, Kimura S, et al. Expression of regulator of G protein signaling protein 5 (RGS5) in the tumor vasculature of human renal cell carcinoma. J Pathol 2004; 203: 551–558.
- 35 Chang SH, Liu CH, Conway R, et al. Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression. Proc Natl Acad Sci USA 2004; 101: 591–596.
- 36 Melyyk O, Shuman MA, Kim KJ. Vascular endothelial growth factor promotes tumor dissemination by a mechanism distinct from its effect on primary tumor growth. Cancer Res 1996; 56: 921–924.
- 37 Matrisan LM. Metalloproteinases and their inhibitors in matrix remodelling. Trends Genet 1990; 6: 121–125.
- 38 Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM. Matrix metalloproteinases: Biologic activity and clinical implications. J Clin Oncol 2000; 18: 1135–1149.
- 39 Zeng ZS, Huang Y, Cohen AM, Guillem JG. Prediction of colorectal cancer relapse and survival via tissue RNA levels of matrix metalloproteinase-9. J Clin Oncol 1996; 14: 3133–3140.
- 40 Tsujii M, Kawano S, Dubois RN. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 1997; 94: 3336–3340.
- 41 Ogawa M, Yamamoto H, Nagano H, et al. Hepatic expression of Ang-2 RNA in metastatic colorectal cancer. Hepatology 2004; 39: 528–539.
- 42 Yoshidome H, Kohno H, Shida T, et al. Significance of monocyte chemoattractant protein-1 in angiogenesis and survival in colorectal liver metastases. Int J Oncol 2009; 34: 923–930.
- 43 Tanaka S, Tatsuguchi A, Futagami S, et al. Monocyte chemoattractant protein 1 and macrophage cyclooxygenase 2 expression in colonic adenoma. Gut 2006; 55: 54–61.
- 44 Nakashima E, Mukaida N, Kubota Y, et al. Human MCAF gene transfer enhances the metastatic capacity of a mouse cachectic adenocarcinoma cell line in vivo. Pharm Res 1995; 12: 1598–1604.
- 45 Muta M, Matsumoto G, Nakashima E, Toi M. Mechanical analysis of tumor growth regression by the cyclooxygenase-2 inhibitor, DFU, in a walker 256 rat tumor model: Importance of monocyte chemoattractant protein-1 modulation. Clin Cancer Res 2006; 12: 264–272.
- 46 Nakashima E, Oya A, Kubota Y, et al. A candidate for cancer gene therapy: MIP-1α gene transfer to an adenocarcinoma cell line reduced tumorigenicity and induced protective immunity in immunocompetent mice. Pharm Res 1996; 13: 1896–1901.
- 47 Cho M, Gwaka J, Parka S, et al. Diclofenac attenuates Wnt/β-catenin signaling in colon cancer cells by activation of NF-κB. FEBS Lett 2005; 579: 4213–4218.
