J Appl Biomed 16:320-327, 2018 | DOI: 10.1016/j.jab.2018.03.002

Chemopreventive action of non-steroidal anti-inflammatory drugs in 9,10-dimethylbenzanthracene induced lung carcinogenesis in BALB/C mice: Expression of COX-1, COX-2 and Nf-κB

Ravi Kishore Sainia, Sankar Nath Sanyala, Jasvinder Singh Bhattib,*
a Panjab University, Department of Biophysics, Chandigarh, India
b Sri Guru Gobind Singh College, Department of Biotechnology, Chandigarh, 160019, India

Non-steroidal anti-inflammatory drugs (NSAIDs) play an effective chemopreventive action against a variety of cancers. The present study aimed at targeting pro-inflammatory cyclooxygenase (COX) and NF-kB mediated inflammatory pathways in 9,10-dimethylbenzanthracene (DMBA) induced lung cancer in BALB/C mice and chemoprotective action of NSAIDs. Animals were divided into five groups and treated with NSAIDs, intratracheally, daily for a period of 18 weeks. Group 1 as control, received vehicle treatment; Group 2 received single dose of DMBA (10 mg/kg bw); Group 3, 4 and 5 besides DMBA treatment, also received Aspirin (60 mg/kg bw), Celecoxib (6.0 mg/kg bw) and Etoricoxib (0.6 mg/kg bw), respectively. DMBA induce DNA damage, apoptosis and expression of COX-1, COX-2 and NF-κB using immunofluorescence and blot analysis were done. The present study demonstrated the formation of micronuclei, over-expression of COX-2 and NF-κB in DMBA induced lung tumorigenesis and thereby suggesting a marked role of inflammation in the tumour progression. Results indicate the formation of micronuclei in DMBA group, which were significantly reduced in aspirin treated group, and totally absent in the celecoxib and etoricoxib groups. In conclusion, co-administration of etoricoxib and celecoxib has significantly reduced the inflammatory potential of the growing neoplasm in DMBA induced lung cancer in male BALB/C mice.

Keywords: Non-steroidal anti-inflammatory drugs; COX-1; COX-2; NF-κB; Inflammation; Lung cancer

Received: December 27, 2017; Accepted: March 12, 2018; Published: November 1, 2018  Show citation

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Saini RK, Nath Sanyal S, Singh Bhatti J. Chemopreventive action of non-steroidal anti-inflammatory drugs in 9,10-dimethylbenzanthracene induced lung carcinogenesis in BALB/C mice: Expression of COX-1, COX-2 and Nf-κB. J Appl Biomed. 2018;16(4):320-327. doi: 10.1016/j.jab.2018.03.002.
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    References

    1. Antonakopoulos, N., Karamanolis, D.G., 2007. The role of NSAIDs in colon cancer prevention. Hepatogastroenterology 54 (78), 1694-1700. Go to PubMed...
    2. Aruoma, O.I., Halliwell, B., 1988. The iron-binding and hydroxyl radical scavenging action of anti-inflammatory drugs. Xenobiotica 18 (4), 459-470. Go to original source... Go to PubMed...
    3. Baker, A.J., Mooney, A., Hughes, J., Lombardi, D., Johnson, R.J., Savill, J., 1994. Mesangial cell apoptosis: the major mechanism for resolution of glomerular hypercellularity in experimental mesangial proliferative nephritis. J. Clin. Invest. 94 (5), 2105-2116. Go to original source... Go to PubMed...
    4. Balakrishnan, S., Menon, V.P., Manoharan, S., Rajalingam, K., 2007. Antigenotoxic effect of ferulic acid in 7,12-dimethyl benz(a)-anthracene (DMBA) induced genotoxicity. Afr. J. Tradit. Complement. Altern. Med. 5 (1), 32-38. Go to original source... Go to PubMed...
    5. Ballaz, S., Mulshine, J.L., 2003. The potential contributions of chronic inflammation to lung carcinogenesis. Clin. Lung Cancer 5 (1), 46-62. Go to original source... Go to PubMed...
    6. Bilani, N., Bahmad, H., Abou-Kheir, W., 2017. Prostate cancer and aspirin use: synopsis of the proposed molecular mechanisms. Front. Pharmacol. 8, 145. Go to original source... Go to PubMed...
    7. Campa, D., Zienolddiny, S., Maggini, V., Skaug, V., Haugen, A., Canzian, F., 2004. Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer. Carcinogenesis 25 (2), 229-235. Go to original source... Go to PubMed...
    8. Cao, Y., Nishihara, R., Wu, K., Wang, M., Ogino, S., Willett, W.C., et al., 2016. Population-wide impact of long-term use of aspirin and the risk for cancer. JAMA Oncol. 2 (6), 762-769. Go to original source... Go to PubMed...
    9. Chandrasekharan, N.V., Dai, H., Roos, K.L., Evanson, N.K., Tomsik, J., Elton, T.S., et al., 2002. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc. Natl. Acad. Sci. U. S. A. 99 (21), 13926-13931. Go to original source... Go to PubMed...
    10. Cheng, K.C., Loeb, L.A., 1997. Genomic stability and instability: a working paradigm. Curr. Top. Microbiol. Immunol. 221, 5-18. Go to original source... Go to PubMed...
    11. Colby, T.V., Wistuba, I.I., Gazdar, A., 1998. Precursors to pulmonary neoplasia. Adv. Anat. Pathol. 5 (4), 205-215. Go to original source... Go to PubMed...
    12. Collins, T.S., Lee, L.F., Ting, J.P., 2000. Paclitaxel up-regulates interleukin-8 synthesis in human lung carcinoma through an NF-kappaB- and AP-1-dependent mechanism. Cancer Immunol. Immunother. 49 (2), 78-84. Go to original source... Go to PubMed...
    13. Cosme, R., Lublin, D., Takafuji, V., Lynch, K., Roche, J.K., 2000. Prostanoids in human colonic mucosa: effects of inflammation on PGE(2) receptor expression. Hum. Immunol. 61 (7), 684-696. Go to original source... Go to PubMed...
    14. Coussens, L.M., Werb, Z., 2002. Inflammation and cancer. Nature 420 (6917), 860- 867. Go to original source... Go to PubMed...
    15. Cryer, B., 2003. The role of cyclooxygenase selective inhibitors in the gastrointestinal tract. Curr. Gastroenterol. Rep. 5 (6), 453-458. Go to original source... Go to PubMed...
    16. Folkman, J., Shing, Y., 1992. Angiogenesis. J. Biol. Chem. 267 (16), 10931-10934. Go to original source...
    17. Gaziev, A.I., Sologub, G.R., Fomenko, L.A., Zaichkina, S.I., Kosyakova, N.I., Bradbury, R. J., 1996. Effect of vitamin-antioxidant micronutrients on the frequency of spontaneous and in vitro gamma-ray-induced micronuclei in lymphocytes of donors: the age factor. Carcinogenesis 17 (3), 493-499. Go to original source... Go to PubMed...
    18. Ghanghas, P., Jain, S., Rana, C., Sanyal, S.N., 2016. Chemoprevention of colon cancer through inhibition of angiogenesis and induction of apoptosis by nonsteroidal anti-inflammatory drugs. J. Environ. Pathol. Toxicol. Oncol. 35 (3), 273-289. Go to original source... Go to PubMed...
    19. Hayashi, M., 2007. In vivo rodent micronucleus assay. In: Obe, G., Vijayalaxmi (Eds.), Chromosomal Alterations. Springer Verlag, Berlin, pp. 257-270. Go to original source...
    20. Hosomi, Y., Yokose, T., Hirose, Y., Nakajima, R., Nagai, K., Nishiwaki, Y., et al., 2000. Increased cyclooxygenase 2 (COX-2) expression occurs frequently in precursor lesions of human adenocarcinoma of the lung. Lung Cancer 30 (2), 73-81. Go to original source... Go to PubMed...
    21. Huang, C., Taki, T., Adachi, M., Konishi, T., Higashiyama, M., Miyake, M., 1998. Mutations in exon 7 and 8 of p53 as poor prognostic factors in patients with non-small cell lung cancer. Oncogene 16 (19), 2469-2477. Go to original source... Go to PubMed...
    22. Karin, M., Greten, F.R., 2005. NF-kB: linking inflammation and immunity to cancer development and progression. Nat. Rev. Immunol. 5 (10), 749-759. Go to original source... Go to PubMed...
    23. Karin, M., Cao, Y., Greten, F.R., Li, Z.-W., 2002. NF-kB in cancer: from innocent bystander to major culprit. Nat. Rev. Cancer 2 (4), 301-310. Go to original source... Go to PubMed...
    24. Koncic, M.Z., Rajic, Z., Petric, N., Zorc, B., 2009. Antioxidant activity of NSAID hydroxamic acids. Acta Pharm. 59 (2), 235-242. Go to original source... Go to PubMed...
    25. Lanas, A., Garcia-Rodriguez, L.A., Arroyo, M.T., Gomollon, F., Feu, F., Gonzalez-Perez, A., et al., 2006. Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations. Gut 55 (12), 1731-1738. Go to original source... Go to PubMed...
    26. Lavnikova, N., Prokhorova, S., Helyar, L., Laskin, D.L., 1993. Isolation and partial characterization of subpopulations of alveolar macrophages, granulocytes, and highly enriched interstitial macrophages from rat lung. Am. J. Respir. Cell Mol. Biol. 8 (4), 384-392. Go to original source... Go to PubMed...
    27. Lee, S.H., Seo, M.J., Choi, S.M., Sohn, Y.S., Kang, K.K., Ahn, B.O., et al., 2005. DA-9201 shows anti-asthmatic effects by suppressing NF-kappaB expression in an ovalbumin-induced mouse model of asthma. Arch. Pharm. Res. 28 (12), 1350- 1357. Go to original source... Go to PubMed...
    28. Luo, J.L., Kamata, H., Karin, M., 2005. The anti-death machinery in IKK/NF-kappaB signalling. J. Clin. Immunol. 25 (6), 541-550. Go to original source... Go to PubMed...
    29. Meisner, L.F., Inhorn, S.L., 1972. Chemically-induced chromosome changes in human cells in vitro. Acta Cytol. 16 (1), 41-47.
    30. Mercadante, S., 2005. Looking for the role of NSAIDs in cancer pain. J. Clin. Oncol. 23 (10), 2442-2443. Go to original source... Go to PubMed...
    31. Miller, K.D., Siegel, R.L., Lin, C.C., Mariotto, A.B., Kramer, J.L., Rowland, J.H., et al., 2016. Cancer treatment and survivorship statistics. CA Cancer J. Clin. 66 (4), 271-289. Go to original source... Go to PubMed...
    32. Mitsiades, N., Mitsiades, C.S., Poulaki, V., Chauhan, D., Richardson, P.G., Hideshima, T., et al., 2002. Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications. Blood 99 (11), 4079-4086. Go to original source... Go to PubMed...
    33. Mosmann, T., 1983. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 65 (1- 2), 55-63. Go to original source... Go to PubMed...
    34. Naugler, W.E., Karin, M., 2008. NF-kB and cancer - identifying targets and mechanisms. Curr. Opin. Genet. Dev. 18 (1), 19-26. Go to original source... Go to PubMed...
    35. Olofsson, B., Pajusola, K., von Euler, G., Chilov, D., Alitalo, K., Eriksson, U., 1996. Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform. J. Biol. Chem. 271 (32), 19310-19317. Go to original source... Go to PubMed...
    36. Olsen, J.H., Friis, S., Poulsen, A.H., Fryzek, J., Harving, H., Tjonneland, A., et al., 2008. Use of NSAIDs, smoking and lung cancer risk. Br. J. Cancer 98 (1), 232-237. Go to original source... Go to PubMed...
    37. Petkova, D.K., Clelland, C., Ronan, J., Pang, L., Coulson, J.M., Lewis, S., et al., 2004. Overexpression of cyclooxygenase-2 in non-small cell lung cancer. Respir. Med. 98 (2), 164-172. Go to original source... Go to PubMed...
    38. Rishikesh, M.K., Sadhana, S.S., 2003. Prostaglandins and cyclooxygenase: their probable roles in cancer. Indian J. Pharmacol. 35 (1), 3-12.
    39. Saini, R.K., Sanyal, S.N., 2008. Pulmonary carcinogenesis in mice with a single intratracheal instillation of 9, 10-dimethyl benz[a]anthracene. Drug Chem. Toxicol. 31 (4), 459-471. Go to original source... Go to PubMed...
    40. Saini, R.K., Sanyal, S.N., 2009. Chemopreventive effect of nonsteroidal antiinflammatory drugs on 9, 10-dimethylbenz[a]anthracene-induced lung carcinogenesis in mice. Oncol. Res. 17 (11-12), 505-518. Go to original source... Go to PubMed...
    41. Saini, M.K., Sanyal, S.N., 2012. PTEN regulates apoptotic cell death through PI3-K/ Akt/GSK3beta signalling pathway in DMH induced early colon carcinogenesis in rat. Exp. Mol. Pathol. 93 (1), 135-146. Go to original source... Go to PubMed...
    42. Saini, M.K., Sharma, P., Kaur, J., Sanyal, S.N., 2009. The cyclooxygenase-2 inhibitor etoricoxib is a potent chemopreventive agent of colon carcinogenesis in the rat model. J. Environ. Pathol. Toxicol. Oncol. 28 (1), 39-46. Go to original source... Go to PubMed...
    43. Saini, M.K., Sanyal, S.N., Vaiphei, K., 2012a. Piroxicam and C-phycocyanin mediated apoptosis in 1,2-dimethylhydrazine dihydrochloride induced colon carcinogenesis: exploring the mitochondrial pathway. Nutr. Cancer 64 (3), 409- 418. Go to original source... Go to PubMed...
    44. Saini, M.K., Vaiphei, K., Sanyal, S.N., 2012b. Chemoprevention of DMH-induced rat colon carcinoma initiation by combination administration of piroxicam and Cphycocyanin. Mol. Cell. Biochem. 361 (1-2), 217-228. Go to original source... Go to PubMed...
    45. Schreinemachers, D.M., Everson, R.B., 1994. Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology 5 (2), 138-146. Go to original source... Go to PubMed...
    46. Shishodia, S., Koul, D., Aggarwal, B.B., 2004. Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates TNF-induced NF-kappa B activation through inhibition of activation of I kappa B alpha kinase and Akt in human non-small cell lung carcinoma: correlation with suppression of COX-2 synthesis. J. Immunol. 173 (3), 2011-2022. Go to original source... Go to PubMed...
    47. Solinas, G., Germano, G., Mantovani, A., Allavena, P., 2009. Tumour-associated macrophages (TAM) as major players of the cancer-related inflammation. J. Leukoc. Biol. 86 (5), 1065-1073. Go to original source... Go to PubMed...
    48. Stark, L.A., Reid, K., Sansom, O.J., Din, F.V., Guichard, S., Mayer, I., et al., 2007. Aspirin activates the NF-kappaB signalling pathway and induces apoptosis in intestinal neoplasia in two in vivo models of human colorectal cancer. Carcinogenesis 28 (5), 968-976. Go to original source... Go to PubMed...
    49. Stewart, B.W., Wild, P. (Eds.), 2014. World Cancer Report 2014. IARC, Copenhagen.
    50. Strober, W., 2001. Trypan blue exclusion test of cell viability. Curr. Protoc. Immunol. 21 (3B) doi:http://dx.doi.org/10.1002/0471142735.ima03bs21A.3B.1-A.3B.2 Appendix CB. Go to original source... Go to PubMed...
    51. Sudheer Kumar, M., Unnikrishnan, M.K., Uma Devi, P., 2003. Effect of 5aminosalicylic acid on radiation-induced micronuclei in mouse bone marrow. Mutat. Res. 527 (1-2), 7-14. Go to original source... Go to PubMed...
    52. Sugunadevi, G., Suresh, K., Vijayaanand, M.A., Rajalingam, K., Sathiyapriya, J., 2012. Anti-genotoxic effect of Mosinone-A on 7, 12-dimethyl benz[a] anthracene induced genotoxicity in male golden Syrian hamsters. Pathol. Oncol. Res. 18 (1), 69-77. Go to original source... Go to PubMed...
    53. Surh, Y.J., Chun, K.S., Cha, H.H., Han, S.S., Keum, Y.S., Park, K.K., et al., 2001. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat. Res. 480-481, 243-268. Go to original source... Go to PubMed...
    54. Sweeney, C., Li, L., Shanmugam, R., Bhat-Nakshatri, P., Jayaprakasan, V., Baldridge, L. A., et al., 2004. Nuclear factor-kappaB is constitutively activated in prostate cancer in vitro and is overexpressed in prostatic intraepithelial neoplasia and adenocarcinoma of the prostate. Clin. Cancer Res. 10 (16), 5501-5517. Go to original source... Go to PubMed...
    55. Tak, P.P., Firestein, G.S., 2001. NF-kB: a key role in inflammatory diseases. J. Clin. Invest. 107 (1), 7-11. Go to original source... Go to PubMed...
    56. Tanabe, T., Tohnai, N., 2002. Cyclooxygenase isozymes and their gene structures and expression. Prostaglandins Other Lipid Mediat. 68-69, 95-114. Go to original source... Go to PubMed...
    57. Tang, X., Liu, D., Shishodia, S., Ozburn, N., Behrens, C., Lee, J.J., et al., 2006. Nuclear factor-kB (nf-kB) is frequently expressed in lung cancer and preneoplastic lesions. Cancer 107 (11), 2637-2646. Go to original source... Go to PubMed...
    58. Thun, M.J., Henley, S.J., Patrono, C., 2002. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J. Natl. Cancer Inst. 94 (4), 252-266. Go to original source... Go to PubMed...
    59. Torisu, H., Ono, M., Kiryu, H., Furue, M., Ohmoto, Y., Nakayama, J., et al., 2000. Macrophage infiltration correlates with tumour stage and angiogenesis in human malignant melanoma: possible involvement of TNFalpha and IL-1alpha. Int. J. Cancer 85 (2), 182-188. Go to original source...
    60. Tsujii, M., DuBois, R.N., 1995. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell 83 (3), 493-501. Go to original source... Go to PubMed...
    61. Tsurutani, J., Castillo, S.S., Brognard, J., Granville, C.A., Zhang, C., Gills, J.J., et al., 2005. Tobacco components stimulate Akt-dependent proliferation and NFkappaBdependent survival in lung cancer cells. Carcinogenesis 26 (7), 1182-1195. Go to original source... Go to PubMed...
    62. Ulrich, C.M., Bigler, J., Potter, J.D., 2006. Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat. Rev. Cancer 6 (2), 130-140. Go to original source... Go to PubMed...
    63. Vaish, V., Piplani, H., Rana, C., Vaiphei, K., Sanyal, S.N., 2013. NSAIDs may regulate EGR-1-mediated induction of reactive oxygen species and non-steroidal antiinflammatory drug-induced gene (NAG)-1 to initiate intrinsic pathway of apoptosis for the chemoprevention of colorectal cancer. Mol. Cell. Biochem. 378 (1-2), 47-64. Go to original source... Go to PubMed...
    64. Venkatesh, P., Shantala, B., Jagetia, G.C., Rao, K.K., Baliga, M.S., 2007. Modulation of doxorubicin-induced genotoxicity by Aegle marmelos in mouse bone marrow: a micronucleus study. Integr. Cancer Ther. 6 (1), 42-53. Go to original source... Go to PubMed...
    65. Wang, X., Li, X., Li, Y., 2007. A modified Coomassie Brilliant Blue staining method at nanogram sensitivity compatible with proteomic analysis. Biotechnol. Lett. 29 (10), 1599-1603. Go to original source... Go to PubMed...
    66. White, E.S., Livant, D.L., Markwart, S., Arenberg, D.A., 2001. Monocyte-fibronectin interactions, via alpha(5)beta(1) integrin, induce expression of CXC chemokinedependent angiogenic activity. J. Immunol. 167 (9), 5362-5366. Go to original source... Go to PubMed...
    67. Wolff, H., Saukkonen, K., Anttila, S., Karjalainen, A., Vainio, H., Ristimaki, A., 1998. Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res. 58 (22), 4997-5001. Go to PubMed...
    68. Wu, P.A., Loh, C.H., Hsieh, L.L., Liu, T.Y., Chen, C.J., Liou, S.H., 2004. Clastogenic effect for cigarette smoking but not areca quid chewing as measured by micronuclei in exfoliated buccal mucosal cells. Mutat. Res. 562 (1-2), 27-38. Go to original source... Go to PubMed...

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