Skip to main content

Advertisement

SpringerLink
Log in

Novel non-cyclooxygenase inhibitory derivatives of naproxen for colorectal cancer chemoprevention

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

A structure-based medicinal chemistry strategy was applied to design new naproxen derivatives that show growth inhibitory activity against human colon tumor cells through a cyclooxygenase (COX)-independent mechanism. In vitro testing of the synthesized compounds against the human HT-29 colon tumor cell line revealed enhanced growth inhibitory activity compared to the parent naproxen with 3a showing IC50 of 11.4 μM (two orders of magnitude more potent than naproxen). Selectivity of 3a was investigated against a panel of three tumor and one normal colon cell lines and showed up to six times less toxicity against normal colonocytes. Compound 3a was shown to induce dose-dependent apoptosis of HT116 colon tumor cells as evidenced by measuring the activity of caspases-3 and 7. None of the synthesized compounds showed activity against COX-1 or COX-2 isozymes, confirming a COX-independent mechanism of action. Compound 3k was found to have no ulcerogenic effect in rats as indicated by electron microscope scanning of the stomach after oral administration. A pharmacophore model was developed for elucidating structure–activity relationships and subsequent chemical optimization for this series of compounds as colorectal cancer chemopreventive drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Scheme 1
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Beck D, Roberts P, Rombeau J, Stamos M, Wexner S (2009) Colorectal cancer: epidemiology, etiology, and molecular basis. In: Wexner SD, Stamos MJ, Rombeau J, Roberts PL, Beck DE (eds) The ASCRS manual of colon and rectal surgery. Springer New York, New York, p 463–484. doi:10.1007/b12857_23

  • Cannon CP, Cannon PJ (2012) COX-2 inhibitors and cardiovascular risk. Science 336(6087):1386–1387. doi:10.1126/science.1224398

    Article  CAS  PubMed  Google Scholar 

  • Chan TA (2002) Nonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancer chemoprevention. Lancet Oncol 3(3):166–174. doi:10.1016/S1470-2045(02)00680-0

    Article  CAS  PubMed  Google Scholar 

  • de Groot DJA, de Vries EGE, Groen HJM, de Jong S (2007) Non-steroidal anti-inflammatory drugs to potentiate chemotherapy effects: From lab to clinic. Crit Rev Oncol Hematol 61(1):52–69. doi:10.1016/j.critrevonc.2006.07.001

    Article  PubMed  Google Scholar 

  • Elsheikh W, Wallace J (2012) P7 Chemo-preventative effects of a hydrogen sulfide-releasing naproxen derivative (ATB-346) in murine colorectal cancer. Nitric Oxide 27(2):S14. doi:10.1016/j.niox.2012.08.008

    Article  Google Scholar 

  • Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Ascherio A, Willett WC (1994) Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Intern Med 121(4):241–246. doi:10.7326/0003-4819-121-4-199408150-00001

    Article  CAS  PubMed  Google Scholar 

  • Grösch S, Maier TJ, Schiffmann S, Geisslinger G (2006) Cyclooxygenase-2 (COX-2)-independent anticarcinogenic effects of selective COX-2 inhibitors. J Natl Cancer Inst 98(11):736–747. doi:10.1093/jnci/djj206

    Article  PubMed  Google Scholar 

  • Hanif R, Pittas A, Feng Y, Koutsos MI, Qiao L, Staiano-Coico L, Shiff SI, Rigas B (1996) Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. Biochem Pharmacol 52(2):237–245. doi:10.1016/0006-2952(96)00181-5

    Article  CAS  PubMed  Google Scholar 

  • Harris RE (2009) Cyclooxygenase-2 (COX-2) blockade in the chemoprevention of cancers of the colon, breast, prostate, and lung. Inflammopharmacology 17(2):55–67. doi:10.1007/s10787-009-8049-8

    Article  CAS  PubMed  Google Scholar 

  • Harris R, Beebe-Donk J, Alshafie G (2008) Similar reductions in the risk of human colon cancer by selective and nonselective cyclooxygenase-2 (COX-2) inhibitors. BMC Cancer 8(1):237

    Article  PubMed Central  PubMed  Google Scholar 

  • Hughes A, Saunders FR, Wallace HM (2012) Naproxen causes cytotoxicity and induces changes in polyamine metabolism independent of cyclo-oxygenase expression. Toxicol Res 1(2):108–115. doi:10.1039/c2tx20018j

    Article  CAS  Google Scholar 

  • Ibrahim T, Rashad A, Abdel-Samii Z, El-Feky S, Abdel-Hamid M, Barakat W (2012) Synthesis, molecular modeling and anti-inflammatory screening of new 1,2,3-benzotriazinone derivatives. Med Chem Res 21(12):4369–4380. doi:10.1007/s00044-012-9975-3

    Article  CAS  Google Scholar 

  • Ishikawa T-O, Herschman HR (2010) Tumor formation in a mouse model of colitis-associated colon cancer does not require COX-1 or COX-2 expression. Carcinogenesis 31(4):729–736. doi:10.1093/carcin/bgq002

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jana NR (2008) NSAIDs and apoptosis. Cell Mol Life Sci 65(9):1295–1301. doi:10.1007/s00018-008-7511-x

    Article  CAS  PubMed  Google Scholar 

  • Khan Z, Khan N, Tiwari RP, Sah NK, Prasad G, Bisen PS (2011) Biology of COX-2: an application in cancer therapeutics. Current Drug Targets 12(7):1082–1093. doi:10.2174/138945011795677764

    Article  CAS  PubMed  Google Scholar 

  • Kune GA, Kune S, Watson LF (1988) Colorectal cancer risk, chronic illnesses, operations, and medications: case control results from the Melbourne Colorectal Cancer Study. Cancer Res 48(15):4399–4404

    CAS  PubMed  Google Scholar 

  • Lanas A (2009) Nonsteroidal antiinflammatory drugs and cyclooxygenase inhibition in the gastrointestinal tract: a trip from peptic ulcer to colon cancer. Am J Med Sci 338(2):96–106. doi:10.1097/MAJ.1090b1013e3181ad1098cd1093

    Article  PubMed  Google Scholar 

  • Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30(16):2785–2791. doi:10.1002/jcc.21256

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Narayanan R, Kim HN, Narayanan NK, Nargi D, Narayanan B (2012) Epidermal growth factor-stimulated human cervical cancer cell growth is associated with EGFR and cyclin D1 activation, independent of COX-2 expression levels. Int J Oncol 40(1):13–20

    CAS  PubMed  Google Scholar 

  • Piazza GA, Alberts DS, Hixson LJ, Paranka NS, Li H, Finn T, Bogert C, Guillen JM, Brendel K, Gross PH, Sperl G, Ritchie J, Burt RW, Ellsworth L, Ahnen DJ, Pamukcu R (1997) Sulindac sulfone inhibits azoxymethane-induced colon carcinogenesis in rats without reducing prostaglandin levels. Cancer Res 57(14):2909–2915

    CAS  PubMed  Google Scholar 

  • Piazza GA, Keeton AB, Tinsley HN, Gary BD, Whitt JD, Mathew B, Thaiparambil J, Coward L, Gorman G, Li Y, Sani B, Hobrath JV, Maxuitenko YY, Reynolds RC (2009) A novel sulindac derivative that does not inhibit cyclooxygenases but potently inhibits colon tumor cell growth and induces apoptosis with antitumor activity. Cancer Prev Res 2(6):572–580. doi:10.1158/1940-6207.capr-09-0001

    Article  CAS  Google Scholar 

  • Radwan A, Al-Dhfyan A, Abdel-Hamid M, Al-Badr A, Aboul-Fadl T (2012) 3,5-Disubstituted thiadiazine-2-thiones: new cell-cycle inhibitors. Arch Pharm Res 35(1):35–49. doi:10.1007/s12272-012-0104-0

    Article  CAS  PubMed  Google Scholar 

  • Rainsford KD (1999) Profile and mechanisms of gastrointestinal and other side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Am J Med 107(6):27–35. doi:10.1016/S0002-9343(99)00365-4

    Article  Google Scholar 

  • Richter M, Weiss M, Weinberger I, Fürstenberger G, Marian B (2001) Growth inhibition and induction of apoptosis in colorectal tumor cells by cyclooxygenase inhibitors. Carcinogenesis 22(1):17–25. doi:10.1093/carcin/22.1.17

    Article  CAS  PubMed  Google Scholar 

  • Sangha S, Yao M, Wolfe MM (2005) Non-steroidal anti-inflammatory drugs and colorectal cancer prevention. Postgrad Med J 81(954):223–227. doi:10.1136/pgmj.2003.008227

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Steele VE, Rao CV, Zhang Y, Patlolla J, Boring D, Kopelovich L, Juliana MM, Grubbs CJ, Lubet RA (2009) Chemopreventive efficacy of naproxen and nitric oxide–naproxen in rodent models of colon, urinary bladder, and mammary cancers. Cancer Prev Res 2(11):951–956. doi:10.1158/1940-6207.capr-09-0080

    Article  CAS  Google Scholar 

  • Suh N, Reddy BS, DeCastro A, Paul S, Lee HJ, Smolarek AK, So JY, Simi B, Wang CX, Janakiram NB, Steele V, Rao CV (2011) Combination of atorvastatin with sulindac or naproxen profoundly inhibits colonic adenocarcinomas by suppressing the p65/β-catenin/cyclin D1 signaling pathway in rats. Cancer Prev Res 4(11):1895–1902. doi:10.1158/1940-6207.capr-11-0222

    Article  CAS  Google Scholar 

  • Thun MJ, Namboodiri MM, Heath CW (1991) Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 325(23):1593–1596. doi:10.1056/NEJM199112053252301

    Article  CAS  PubMed  Google Scholar 

  • Tinsley H, Grizzle W, Abadi A, Keeton A, Zhu B, Xi Y, Piazza G (2013) New NSAID Targets and Derivatives for colorectal cancer chemoprevention. In: Chan AT, Detering E (eds) Prospects for chemoprevention of colorectal neoplasia, vol 191. Recent results in cancer research. Springer, Berlin, p 105–120. doi:10.1007/978-3-642-30331-9_6

  • Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, Egger M, Jüni P (2011) Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 342. doi:10.1136/bmj.c7086

  • Tuynman JB, Peppelenbosch MP, Richel DJ (2004) COX-2 inhibition as a tool to treat and prevent colorectal cancer. Crit Rev Oncol Hematol 52(2):81–101

    Article  CAS  PubMed  Google Scholar 

  • Vane JR, Botting RM (1996) Mechanism of action of anti-inflammatory drugs. Scand J Rheumatol 25(s102):9–21. doi:10.3109/03009749609097226

    Article  Google Scholar 

  • Wang D, DuBois RN (2009) The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene 29(6):781–788

    Article  PubMed Central  PubMed  Google Scholar 

  • Whitt JD, Li N, Tinsley HN, Chen X, Zhang W, Li Y, Gary BD, Keeton AB, Xi Y, Abadi AH, Grizzle WE, Piazza GA (2012) A novel sulindac derivative that potently suppresses colon tumor cell growth by inhibiting cGMP phosphodiesterase and β-catenin transcriptional activity. Cancer Prev Res 5(6):822–833. doi:10.1158/1940-6207.capr-11-0559

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors acknowledge Jason D. Whitt (University of Alabama at Birmingham) for performing cyclooxygenase assays.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia

    Tarek Aboul-Fadl & Suliman S. Al-Hamad

  2. Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt

    Tarek Aboul-Fadl & Mohammed K. Abdel-Hamid

  3. Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA

    Kevin Lee, Bernard D. Gary, Adam B. Keeton & Gary A. Piazza

  4. Department of Biochemistry, The University of Alabama at Birmingham, Birmingham, AL, 35205, USA

    Nan Li

  5. Centre for Chemical Biology, The University of Newcastle, Callaghan, NSW, 2308, Australia

    Mohammed K. Abdel-Hamid

Authors
  1. Tarek Aboul-Fadl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Suliman S. Al-Hamad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kevin Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bernard D. Gary
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Adam B. Keeton
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gary A. Piazza
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mohammed K. Abdel-Hamid
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Tarek Aboul-Fadl or Mohammed K. Abdel-Hamid.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 45 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aboul-Fadl, T., Al-Hamad, S.S., Lee, K. et al. Novel non-cyclooxygenase inhibitory derivatives of naproxen for colorectal cancer chemoprevention. Med Chem Res 23, 4177–4188 (2014). https://doi.org/10.1007/s00044-014-0979-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-014-0979-z

Keywords

Search

Navigation