Dual inhibition of COX-2/5-LOX blocks colon cancer proliferation, migration and invasion in vitro

Che,Xiao-Hang; Chen,Chun-Lin; Ye,Xiao-Lei; Weng,Guo-Bin; Guo,Xian-Zhi; Yu,Wen-Ying; Tao,Jin; Chen,Yi-Chen; Chen,Xiaodong

doi:10.3892/or.2015.4506

Dual inhibition of COX-2/5-LOX blocks colon cancer proliferation, migration and invasion in vitro

Authors:
- Xiao-Hang Che
- Chun-Lin Chen
- Xiao-Lei Ye
- Guo-Bin Weng
- Xian-Zhi Guo
- Wen-Ying Yu
- Jin Tao
- Yi-Chen Chen
- Xiaodong Chen
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Affiliations: Department of Drugs and Pharmacology, Ningbo Institute of Medical Sciences, Ningbo, Zhejiang 315020, P.R. China, College of Chemistry and Bio-Engineering, Yichun University, Yichun, Jiangxi 336000, P.R. China, Department of Urology, Ningbo Urinary Kidney Disease Hospital, Ningbo, Zhejiang 315100, P.R. China, Department of Medical Oncology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China, Ningbo Clinical and Pathology Diagnostic Center, Ningbo, Zhejiang 315021, P.R. China
Published online on: December 22, 2015 https://doi.org/10.3892/or.2015.4506
Pages: 1680-1688

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Abstract

Inflammation is emerging as a new hallmark of cancer. Arachidonic acid (AA) metabolism, the family of cyclooxygenases (COXs) and lipoxygenase (LOX) play important roles in AA-related inflammatory cascades. In 94 colorectal cancer samples collected from the Han population, the immunohistochemical results indicated that 68% of the patients with colorectal cancer had a co-expression of both COX-2 and 5-LOX, while both displayed low expression in the matched normal tissues. In cell lines, three colorectal cancer cell lines exhibited high expression of COX-2 and 5-LOX. During stable silencing of the expression of COX-2 or 5-LOX in LoVo cancer cells, we found that downregulation of either COX-2 or 5-LOX significantly diminished the growth, migration and invasion of the colon cancer cells and specifically, downregulation of COX-2 could elicit upregulation of 5-LOX protein and vice versa. The above results suggested that the simultaneous blocking of COX-2 and 5-LOX activity may bring more potential benefits in managing the progression of colon cancer. Therefore, we sought to explore the effectiveness of a dual COX-2/5-LOX inhibitor darbufelone on the proliferation, migration, invasion and apoptosis of colon cancer cells, as well as the underlying mechanism of action. The results indicated that darbufelone significantly decreased the proliferative and invasive abilities of the colon cancer cells, in a dose-dependent manner. During the study of the related mechanisms, we found an upregulation of p27 and downregulation of cyclin D1 as well as CDK4 after darbufelone treatment, which indicated that darbufelone could arrest the cell cycle of LoVo cells at the G0/G1 phase. Furthermore, the activation of caspase-3 and -9, upregulation of Bax and downregulation of Bcl-2 demonstrated the occurrence of apoptosis by darbufelone. Finally, darbufelone also prevented the migration and invasion of LoVo cells, which may be ascribed to the upregulation of E-cadherin and ZO-1. In summary, our data suggest that the inhibition of both COX-2/5-LOX may be an effective therapeutic approach for colon cancer management, particularly for those patients with high expression of COX-2/5-LOX.

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1	Wang ZX, Cao JX, Liu ZP, Cui YX, Li CY, Li D, Zhang XY, Liu JL and Li JL: Combination of chemotherapy and immunotherapy for colon cancer in China: A meta-analysis. World J Gastroenterol. 20:1095–1106. 2014. View Article : Google Scholar : PubMed/NCBI
2	Sears CL and Garrett WS: Microbes, microbiota, and colon cancer. Cell Host Microbe. 15:317–328. 2014. View Article : Google Scholar : PubMed/NCBI
3	Magalhães B, Peleteiro B and Lunet N: Dietary patterns and colorectal cancer: Systematic review and meta-analysis. Eur J Cancer Prev. 21:15–23. 2012. View Article : Google Scholar
4	Mantovani A: Cancer: Inflaming metastasis. Nature. 457:36–37. 2009. View Article : Google Scholar : PubMed/NCBI
5	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
6	Julémont F, Dogné JM, Pirotte B and de Leval X: Recent development in the field of dual COX/5-LOX inhibitors. Mini Rev Med Chem. 4:633–638. 2004. View Article : Google Scholar
7	Harris RE: Cyclooxygenase-2 (cox-2) blockade in the chemoprevention of cancers of the colon, breast, prostate, and lung. Inflammopharmacology. 17:55–67. 2009. View Article : Google Scholar : PubMed/NCBI
8	DuBois RN, Giardiello FM and Smalley WE: Nonsteroidal anti-inflammatory drugs, eicosanoids, and colorectal cancer prevention. Gastroenterol Clin North Am. 25:773–791. 1996. View Article : Google Scholar : PubMed/NCBI
9	Perumal V, Banerjee S, Das S, Sen RK and Mandal M: Effect of liposomal celecoxib on proliferation of colon cancer cell and inhibition of DMBA-induced tumor in rat model. Cancer Nanotechnol. 2:67–79. 2011. View Article : Google Scholar : PubMed/NCBI
10	Tavolari S, Munarini A, Storci G, Laufer S, Chieco P and Guarnieri T: The decrease of cell membrane fluidity by the non-steroidal anti-inflammatory drug Licofelone inhibits epidermal growth factor receptor signalling and triggers apoptosis in HCA-7 colon cancer cells. Cancer Lett. 321:187–194. 2012. View Article : Google Scholar : PubMed/NCBI
11	Balansky R, Ganchev G, Iltcheva M, Nikolov M, Maestra SL, Micale RT, D'Agostini F, Steele VE and De Flora S: Modulation by licofelone and celecoxib of experimentally induced cancer and preneoplastic lesions in mice exposed to cigarette smoke. Curr Cancer Drug Targets. 15:188–195. 2015. View Article : Google Scholar : PubMed/NCBI
12	Wang D and Dubois RN: Eicosanoids and cancer. Nat Rev Cancer. 10:181–193. 2010. View Article : Google Scholar : PubMed/NCBI
13	Greene ER, Huang S, Serhan CN and Panigrahy D: Regulation of inflammation in cancer by eicosanoids. Prostaglandins Other Lipid Mediat. 96:27–36. 2011. View Article : Google Scholar : PubMed/NCBI
14	Mohammed A, Janakiram NB, Li Q, Choi CI, Zhang Y, Steele VE and Rao CV: Chemoprevention of colon and small intestinal tumorigenesis in APC^Min/+ mice by licofelone, a novel dual 5-LOX/COX inhibitor: Potential implications for human colon cancer prevention. Cancer Prev Res. 4:2015–2026. 2011. View Article : Google Scholar
15	Tavolari S, Bonafè M, Marini M, Ferreri C, Bartolini G, Brighenti E, Manara S, Tomasi V, Laufer S and Guarnieri T: Licofelone, a dual COX/5-LOX inhibitor, induces apoptosis in HCA-7 colon cancer cells through the mitochondrial pathway independently from its ability to affect the arachidonic acid cascade. Carcinogenesis. 29:371–380. 2008. View Article : Google Scholar
16	Acosta KB, Tibolla MM, Tiscornia MM, Lorenzati MA and Zapata PD: Recent patents related to phosphorylation signaling pathway on cancer. Recent Pat DNA Gene Seq. 5:175–184. 2011. View Article : Google Scholar : PubMed/NCBI
17	Hu H, Krasinskas A and Willis J: Perspectives on current tumor-node-metastasis (TNM) staging of cancers of the colon and rectum. Semin Oncol. 38:500–510. 2011. View Article : Google Scholar : PubMed/NCBI
18	Zhu LB, Jiang J, Zhu XP, Wang TF, Chen XY, Luo QF, Shu Y, Liu ZL and Huang SH: Knockdown of Aurora-B inhibits osteosarcoma cell invasion and migration via modulating PI3K/Akt/NF-κB signaling pathway. Int J Clin Exp Pathol. 7:3984–3991. 2014.
19	Coussens LM and Werb Z: Inflammation and cancer. Nature. 420:860–867. 2002. View Article : Google Scholar : PubMed/NCBI
20	Vakkila J and Lotze MT: Inflammation and necrosis promote tumour growth. Nat Rev Immunol. 4:641–648. 2004. View Article : Google Scholar : PubMed/NCBI
21	Agarwal S, Reddy GV and Reddanna P: Eicosanoids in inflammation and cancer: The role of COX-2. Expert Rev Clin Immunol. 5:145–165. 2009. View Article : Google Scholar : PubMed/NCBI
22	Balkwill F and Mantovani A: Inflammation and cancer: Back to Virchow? Lancet. 357:539–545. 2001. View Article : Google Scholar : PubMed/NCBI
23	Harris RE, Chlebowski RT, Jackson RD, Frid DJ, Ascenseo JL, Anderson G, Loar A, Rodabough RJ, White E and McTiernan A; Women's Health Initiative: Breast cancer and nonsteroidal anti-inflammatory drugs: Prospective results from the Women's Health Initiative. Cancer Res. 63:6096–6101. 2003.PubMed/NCBI
24	Wang MT, Honn KV and Nie D: Cyclooxygenases, prostanoids, and tumor progression. Cancer Metastasis Rev. 26:525–534. 2007. View Article : Google Scholar : PubMed/NCBI
25	Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB and Lipsky PE: Cyclooxygenase in biology and disease. FASEB J. 12:1063–1073. 1998.PubMed/NCBI
26	Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S and DuBois RN: Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 107:1183–1188. 1994.PubMed/NCBI
27	Ashok V, Dash C, Rohan TE, Sprafka JM and Terry PD: Selective cyclooxygenase-2 (COX-2) inhibitors and breast cancer risk. Breast. 20:66–70. 2011. View Article : Google Scholar
28	Ferrandina G, Lauriola L, Zannoni GF, Fagotti A, Fanfani F, Legge F, Maggiano N, Gessi M, Mancuso S, Ranelletti FO, et al: Increased cyclooxygenase-2 (COX-2) expression is associated with chemotherapy resistance and outcome in ovarian cancer patients. Ann Oncol. 13:1205–1211. 2002. View Article : Google Scholar : PubMed/NCBI
29	Gupta S, Srivastava M, Ahmad N, Bostwick DG and Mukhtar H: Overexpression of cyclooxygenase-2 in human prostate adenocarcinoma. Prostate. 42:73–78. 2000. View Article : Google Scholar
30	Hida T, Yatabe Y, Achiwa H, Muramatsu H, Kozaki K, Nakamura S, Ogawa M, Mitsudomi T, Sugiura T and Takahashi T: Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res. 58:3761–3764. 1998.PubMed/NCBI
31	Pidgeon GP, Lysaght J, Krishnamoorthy S, Reynolds JV, O'Byrne K, Nie D and Honn KV: Lipoxygenase metabolism: Roles in tumor progression and survival. Cancer Metastasis Rev. 26:503–524. 2007. View Article : Google Scholar : PubMed/NCBI
32	Ye YN, Wu WK, Shin VY, Bruce IC, Wong BC and Cho CH: Dual inhibition of 5-LOX and COX-2 suppresses colon cancer formation promoted by cigarette smoke. Carcinogenesis. 26:827–834. 2005. View Article : Google Scholar : PubMed/NCBI
33	Bishnoi M, Patil CS, Kumar A and Kulkarni SK: Protective effects of nimesulide (COX inhibitor), AKBA (5-LOX inhibitor), and their combination in aging-associated abnormalities in mice. Methods Find Exp Clin Pharmacol. 27:465–470. 2005. View Article : Google Scholar : PubMed/NCBI
34	Pommery N, Taverne T, Telliez A, Goossens L, Charlier C, Pommery J, Goossens JF, Houssin R, Durant F and Hénichart JP: New COX-2/5-LOX inhibitors: Apoptosis-inducing agents potentially useful in prostate cancer chemotherapy. J Med Chem. 47:6195–6206. 2004. View Article : Google Scholar : PubMed/NCBI
35	Smyth EM, Grosser T, Wang M, Yu Y and FitzGerald GA: Prostanoids in health and disease. J Lipid Res. 50(Suppl): S423–S428. 2009. View Article : Google Scholar :