A novel naproxen derivative capable of displaying anti-cancer and anti-migratory properties against human breast cancer cells

BMC Cancer

Jolly Deb²  Joydeb Majumder³  Sankar Bhattacharyya¹  Siddhartha Sankar Jana² 

[1] Department of Zoology, Sidho Kanho Birsha University, Purulia, India

[2] Department of Biological Chemistry, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, 700032 Kolkata, India

[3] Department of Organic Chemistry, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, 700032 Kolkata, India

关键词: Metastasis;    Inflammation;    Apoptosis;    MTT assay;    MDA-MB-231;    MCF-7;   

Others  :  1125237
DOI  :  10.1186/1471-2407-14-567

 received in 2014-02-18, accepted in 2014-07-30,  发布年份 2014

【 摘 要 】

Background

Increasingly, the role of chronic inflammation and its mediators in tumor generation and progression is gaining importance in the field of cancer research. In this context, candidature of non steroidal anti-inflammatory drugs (NSAIDs) as potential anti-tumor therapeutic agent is being evaluated globally. In the present study we have evaluated the anti-cancer effect of a series of newly synthesized naproxen derivatives on human breast cancer cell lines.

Methods

MCF-7 (poorly invasive) and MDA-MB-231 (highly invasive) cells were treated with different concentrations of naproxen sodium and its derivatives in vitro, and the underlying mechanism of action was monitored by employing studies related to induction of apoptosis, activation of caspases, cell-cycle progression, synthesis of PGE₂ and cellular migration.

Results

After a preliminary screening using MCF-7 and MDA-MB-231 cells, it was evident that naproxen derivative 4 has a better killing property compared to its parent compound naproxen sodium (NS). On further investigation, it was apparent that the observed growth inhibitory activity on MDA-MB-231 cells after treatment with 4, was not due to cell cycle arrest but due to an early induction of apoptosis and subsequent induction of caspases 3 and 9. Derivative 4 could also inhibit COX activity in MDA-MB-231 cells as evidenced by reduction in prostaglandin E2 secretion. Moreover, 4 was capable of delaying the overall migration rate of MDA-MB-231 cells in vitro.

Conclusion

In this study we report that a naproxen-derivative (4) has powerful anti-inflammatory and anti-tumor properties as it induces appreciable amount of apoptosis in breast cancer cell line, and can also delay migration of cancer cells (MDA-MB-231) which would in turn delay cancer cell invasion and formation of secondary tumours in primary breast cancer patients. Thus, we propose that 4 is worthy of further investigation due to its potential as a therapeutic agent in anti-tumor treatment regimen.

【 授权许可】

   
2014 Deb et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Balkwill F, Mantovani A: Inflammation and cancer: back to Virchow? Lancet 2001, 357:539-45.
• [2]Shacter E, Weitzman SA: Chronic inflammation and cancer. Oncology 2002, 16:217-26.
• [3]Thun MJ, Henley SJ, Patrono C: Non-steroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst 2002, 94:252-66.
• [4]Baron JA, Sandler RS: Nonsteroidal anti-inflammatory drugs and cancer prevention. Annu Rev Med 2000, 51:511-23.
• [5]Garcia-Rodriguez LA, Huerta-Alvarez C: Reduced risk of colorectal cancer among long-term users of aspirin and nonaspirin nonsteroidal antiinflammatory drugs. Epidemiology 2001, 12:88-93.
• [6]Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ: Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000, 343:1520-28.
• [7]Srinivas S, Feldman D: A Phase II trial of calcitriol and naproxen in recurrent prostate cancer. Anticancer Res 2009, 29:3605-10.
• [8]Suh N, Reddy BS, DeCastro A, Paul S, Lee HJ, Smolarek AK, So JY, Simi B, Wang CX, Janakiram NB, Steele V, Rao CV: Combination of atorvastatin with sulindac or naproxen profoundly inhibits colonic adenocarcinomas by suppressing the p65/b-catenin/cyclin D1 signaling pathway in rats. Cancer Prev Res 2011, 14:1895-902.
• [9]Williams CS, Mann M, DuBois RN: The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 1999, 18:7908-16.
• [10]Ristimaki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C: Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 2002, 62:632-35.
• [11]Basu GD, Pathangey LB, Tinder TL, Gendler SJ, Mukherjee P: Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells. Breast Cancer Res 2005, 7:422-35.
• [12]Chen EP, Smyth EM: COX-2 and PGE2-dependent immunomodulation in breast cancer. Prostaglandins Other Lipid Mediat 2011, 96:14-20.
• [13]Majumder J, Das MR, Deb J, Jana SS, Dastidar P: β-Amino acid and amino- alcohol conjugation of a nonsteroidal anti-inflammatory drug (NSAID) imparts hydrogelation displaying remarkable biostability, biocompatibility, and anti- inflammatory properties. Langmuir 2013, 29:10254-63.
• [14]Bhattacharyya S, Deb J, Patra AK, Thuy Pham DA, Chen W, Vaeth M, Berberich-Siebelt F, Klein-Hessling S, Lamperti ED, Reifenberg K, Jellusova J, Schweizer A, Nitschke L, Leich E, Rosenwald A, Brunner C, Engelmann S, Bommhardt U, Avots A, Muller MR, Kondo E, Serfling E: NFATc1 affects mouse splenic B cell function by controlling the calcineurin--NFAT signaling networ. J Exp Med 2011, 208:823-39.
• [15]Cory G: Scratch-wound assay. Methods Mol Biol 2011, 769:25-30.
• [16]Dunn GP, Old LJ, Schreiber RD: The three Es of cancer immunoediting. Annu Rev Immunol 2004, 22:329-60.
• [17]Mcllwain DR, Berger T, Mak TW: Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol 2013, 5:a008656.
• [18]Hengartner MO: The biochemistry of apoptosis. Nature 2000, 407:770-76.
• [19]Waldman T, Zhang Y, Dillehay L, Yu J, Kinzler K, Vogelstein B, Williams J: Cell-cycle arrest versus cell death in cancer therapy. Nat Med 1997, 3:1034-36.
• [20]Ehrhardt H, Wachter F, Grunert M, Jeremias I: Cell cycle-arrested tumor cells exhibit increased sensitivity towards TRAIL-induced apoptosis. Cell Death Dis 2013, 4:e661.
• [21]Timoshenko AV, Xu G, Chakrabarti S, Lala PK, Chakraborty C: Role of prostaglandin E2 receptors in migration of murine and human breast cancer cells. Exp Cell Res 2003, 289:265-74.
• [22]Nakanishi M, Rosenberg DW: Multifaceted roles of PGE2 in inflammation and cancer. Semin Immunopathol 2013, 35:123-37.
• [23]Wang H, Yang Z: Molecular hydrogels of hydrophobic compounds: a novel self-delivery system for anti-cancer drugs. Soft Matter 2012, 8:2344-47.