Skip to main content

Advertisement

SpringerLink
Log in

Synthesis, characterization and biological evaluation of some new indomethacin analogs with a colon tumor cell growth inhibitory activity

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

Abstract

Focusing particularly on colorectal cancer, and suggesting research strategies that may help to accelerate the future clinical application of indomethacin for the treatment of cancer, the molecular structures of indomethacin was used as starting scaffold to design novel amide analogs, and the effects of those analogs on the proliferation of human cancer cells were evaluated against three colon cancer cell lines, namely, HCT-116, CACO-2, and HT-29. Compared to indomethacin, the new derivatives displayed significantly increased activities. Interestingly two of the indomethacin analogs 7a and 8c displayed high growth inhibitory activity in nano-molar to micro-molar range against all three human colon cancer cell lines with IC50 values ranging from 0.055 to 4.0 µg/ml compared to 0.7–5.45 µg/ml for 5-fluorouracil (5-FU). Moreover, the potential mechanisms of the cytotoxic activity of the promising compounds 7a and 8c on the HT-29 and HCT-116 cell lines respectively were studied. The results indicated that compounds 7a and 8c arrested the cell cycle at G1/S and G0/G1 phase in HT-29 and HCT-116 cells respectively and might induced apoptosis via caspase-3 dependent pathway.

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

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

Similar content being viewed by others

References

  • Alnemri ES, Livingston DJ, Nichoson DW, Salvesen G, Thornberry NA, Wong WW, Yuan T (1996) Human ICE/CED-3 protease nomenclature. Cell 87:171

    Article  CAS  PubMed  Google Scholar 

  • Al-ObaidA M, Abdel-Hamide SG, El-Kashef HA, Abdel-Aziz AAM, El-Azab AS, Al-Khamees HA, El-Subbagh HI (2009) Substituted quinazolines, part 3. Synthesis, in vitro antitumor activity and molecular modeling study of certain 2-thieno-4(3H)-quinazolinone analogs. Eu J Med Chem 44:2379–2391

    Article  Google Scholar 

  • Bertoli C, Skotheim JM, de Bruin RAM (2013) Control of cell cycle transcription during G1 and S phases. Nat Rev Mol Cell Biol 14(8):518–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blidner AG, Salatino M, Mascanfroni ID, Diament MJ, Joffe EK, Jasnis MA, Klein SM, Rabinovich GA (2015) Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent Indomethacin in tumor-associated and tumor-free microenvironments. J Immunol 194:3452–3462

    Article  CAS  PubMed  Google Scholar 

  • Blitzer A, Huang CC (1983) The effect of indomethacin on the growth of epidermoid carcinoma of the palate in rats. Arch Otolaryng 109:719–723

    Article  CAS  PubMed  Google Scholar 

  • Chan TA (2002) Nonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancer chemoprevention. Lancet Oncol 3:166–174

    Article  CAS  PubMed  Google Scholar 

  • Connell JBO, Maggard MA, Ko CY (2014) Colon cancer survival rates with the new American joint committee on cancer sixth edition staging. J Natl Cancer Inst 96:1420–1425

    Article  Google Scholar 

  • Cotter TG (2009) Apoptosis and cancer: the genesis of a research field. Nat Rev Cancer 9(7):501–507

    Article  CAS  PubMed  Google Scholar 

  • Creagh EM, Martin SJ (2001) Caspases: cellular demolition experts. Biochem Soc Trans 29:696–702

    Article  CAS  PubMed  Google Scholar 

  • D’Amelio M (2010) Neuronal caspase-3 signaling: not only cell death. Cell Death Differ 17:1104–1114

    Article  PubMed  Google Scholar 

  • Eissa SI, Farrag AM, Abdel Galeell GA (2013) Non -carboxylic analogues of aryl propionic acid: synthesis, anti-inflammatory, analgesic, antipyretic and ulcerogenic potential. Drug Res 63:1–8

    Article  Google Scholar 

  • Elder DJ, Halton DE, Hague A, Paraskeva C (1997) Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug: independence from COX-2 protein expression. Clin Cancer Res 3:1679–1683

    CAS  PubMed  Google Scholar 

  • Groot DJA, Deen M, Le TKP, Regeling A, Jong S, Vries EGE (2007) Indomethacin induces apoptosis via a MRP1-dependent mechanism in doxorubicin-resistant small-cell lung cancer cells overexpressing MRP1. Br J Cancer 97:1077–1083

    Article  PubMed  PubMed Central  Google Scholar 

  • Groot DJA, Timmer T, Spierings DCJ, Le TKP, Jong S, Vries EGE (2005) Indomethacin-induced activation of the death receptor-mediated apoptosis pathway circumvents acquired doxorubicin resistance in SCLC cells. Br J Cancer 92:1459–1466

    Article  PubMed  PubMed Central  Google Scholar 

  • Hanif R, Pittas A, Feng Y, Koutsos MI, Qiao L, Staiano-Coico L (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

    Article  CAS  PubMed  Google Scholar 

  • Hassan WH, AbuAlmaaty A, Ohba Y, Sakuragi N (2014) Apoptosis and molecular targeting therapy in cancer. Bio Med Res Intern 7:1–23

    Google Scholar 

  • Hawcraft G, Amico MD, Albanese C, Markhom AF, Pestell RG, Kull MA (2002) Indomethacin induces differential expression of beta-catenin, gamma-catenin and T-cell factor target genes in human colorectal cancer cells. Carcinogenesis 23:107–114

    Article  Google Scholar 

  • Heneghan JB (1985) Inhibition of human colon tumor growth in nude mice by indomethacin. In: Liss AR (ed) Germfree research: microflora control and its application to biomedical science, Europe PMC, New York, p 315–318

  • Huang KB, Chen ZF, Liu YC, Li ZQ, Wei JH, Wang M, Zhang GH, Liang H (2013) Platinum(II) complexes with mono-aminophosphonate ester targeting group that induce apoptosis through G1 cell-cycle arrest: synthesis, crystal structure and antitumour activity. Eur J Med Chem 63:76–84

    Article  CAS  PubMed  Google Scholar 

  • Janicke RU, Sprengart ML, Wati MR, Porter AG (1998) Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 273:9357–9360

    Article  CAS  PubMed  Google Scholar 

  • Jones MK, Wang H, Peskar BM, Levin E, Itani RM, Sarfels IJ, Tarnawski AS (1999) Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med 5:1418–1423

    Article  CAS  PubMed  Google Scholar 

  • Kalgutkar AS, Crews BC, Rowlinson SW, Marnett AB, Kozak KR, Remmel RP, Marnett LJ (2000) Biochemically based design of cyclooxygenase-2(COX-2) inhibitors: facile conversion of nonsteroidal antiinflammatory drugs,to potent and highly selective COX-2 inhibitors. Proc Natl Acad Sci 97:925–930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khalifa MMA, Ismail MMF, Eissa SI, Ammar YA (2012) Design and synthesis, of some novel 6-methoxynaphthalene derivatives with potential anti-cancer activity. Der Pharma Chem 4(4):1552–1566

    CAS  Google Scholar 

  • Kim WH, Yeo M, Kim MS, Chun SB, Shin EC, Park JH, Park IS (2000) Role of caspase-3 in apoptosis of colon cancer cells induced by nonsteroidal anti-inflammatory drugs. Int J Colorectal Dis 15:105–111

    Article  CAS  PubMed  Google Scholar 

  • Kralj M, Kapitanovic S, Kovacevic D, Lukac J, Spaventi S, Pavelic K (2001) Effect of the nonsteroidal anti-inflammatory drug indomethacin on proliferation and apoptosis of colon carcinoma cells. J Can Res Clin Oncol 127:173–179

    Article  CAS  Google Scholar 

  • Kumar N, Drabu S, Mondal SC (2013) NSAID’s and selectively COX-2 inhibitors as potential chemoprotective agents against cancer. Arab J Chem 6:1–23

    Article  Google Scholar 

  • Ma H, Deacon S, Horiuchi K (2008) The challenge of selecting protein kinase assays for lead discovery optimization. Expert Opin Drug Discov 3(6):607–621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michael J, Thun S, Henley J, Patrono C (2002) Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues. J Nat Cancer Ins 94:252–266

    Article  Google Scholar 

  • Noolvi MN, Patel HM, Bhardwaj V, Chauhan A (2011) Synthesis and in vitro antitumor activity of substituted quinazoline and quinoxaline derivatives: search for anticancer agent. Eur J Med Chem 46:2327–2346

    Article  CAS  PubMed  Google Scholar 

  • Pan MH, Chen WJ, Lin-Shiau SY, Ho CT, Lin JK (2002) Tangeretin induces cell-cycle G1 arrest through inhibiting cyclin-dependent kinases 2 and 4 activities as well as elevating CdK inhibitors p21 and p27 in human colorectal carcinoma cells. Carcinogenesis 23:1677–1684

    Article  CAS  PubMed  Google Scholar 

  • Piazza GA, Rahm AK, Finn TS (1997) Apoptosis primarily accounts for the growth inhibitory properties of sulindac metabolites and involves a mechanism that is independent of cyclooxygenase inhibition, cell cycle arrest, and p53 induction. Cancer Res 57:2452–2459

    CAS  PubMed  Google Scholar 

  • Piazza GA, Rahm AL, Krutzsch M (1995) Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Res 55:3110–3116

    CAS  PubMed  Google Scholar 

  • Pollard M, Luckert PH (1983) Prolonged antitumor effect of indomethacin on autochthonous intestinal tumors in rats. J Natl Cancer Inst 701:1103–1105

    Google Scholar 

  • Rigas B, Kashfi K (2005) Cancer prevention: a new era beyond cyclooxygenase-2. J Pharmacol Exp Ther 314:1–8

    Article  CAS  PubMed  Google Scholar 

  • Rigas B, Shiff SJ (1999) Nonsteroidal anti-inflammatory drugs and the induction of apoptosis in colon cells: evidence for PHS dependent and PHS-independent mechanisms. Apoptosis 4(5):373–381

    Article  CAS  PubMed  Google Scholar 

  • Schror K (2011) Pharmacology and cellular/molecular mechanisms of action of aspirin and non-aspirin NSAIDs in colorectal cancer. Best Pract Res Clin Gastroenterol 25:473–474

    Article  PubMed  Google Scholar 

  • Sheen JH, Woo JK, Dickson RB (2003) c-Myc alters the DNA damage-induced G2/M arrest in human mammary epithelial cells. Br J Cancer 89:1479–1485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sinha RP, Richa RPR (2009) Apoptosis: molecular mechanisms and pathogenicity. J Exp Clin Sci 8:155–181

    Google Scholar 

  • Tinsley HN, Gary BD, Thaiparambil J, Li N, Lu W, Li Y, Maxuitenko YY, Keeton AB, Piazza GA (2010) Colon tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibition. Cancer Prev Res 3:1303–1313

    Article  CAS  Google Scholar 

  • Watson AJM (2004) Apoptosis and colorectal cancer. Gut 53(11):1701–1709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolter F, Akoglu B, Clausnitzer A, Stein J (2001) Downregulation of the cyclin D1/Cdk4 complex occurs during resveratrolinduced cell cycle arrest in colon cancer cell lines. J Nutr 131:2197–2203

    CAS  PubMed  Google Scholar 

  • Woo M, Hakem R, Soengas MS, Duncan GS, Shahinian A, Kägi D, Hakem A, McCurrach M, Khoo W, Kaufman SA, Senaldi G, Howard T, Mak TW (1998) Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev 12:806–819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu M, Xu X (2001) Induction of apoptosis by cyclooxygenase-2 inhibitor NS398 through a cytochrome C-dependent pathway in esophageal cancer cells. Int J Cancer 93:218

    Article  PubMed  Google Scholar 

  • Zhu GH, Wong BC, Eggo MC, Ching CK, Yuen ST, Chan EY, Lai KC, Lam SK (1999a) Non-steroidal anti-inflammatory drug-induced apoptosis in gastric cancer cells is blocked by protein kinase C activation through inhibition of c-myc. Br J Caner 79:393–400

    Article  CAS  Google Scholar 

  • Zhu GH, Wong BC, Ching CK, Lai KC, Lam SK (1999b) Differential apoptosis by indomethacin in gastric epithelial cells through the constitutive expression of wild-type p53 and/or upregulation of c-myc. Biochem Pharmacol 58:193–200

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author is grateful to all members of Pharmacology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt and confirmatory diagnostic unit VACSERA-EGYPT for carrying out the anticancer screening.

Author information

Authors and Affiliations

  1. Pharmaceutical Chemistry Department, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo, Egypt

    Sally I. Eissa

Authors
  1. Sally I. Eissa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sally I. Eissa.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eissa, S.I. Synthesis, characterization and biological evaluation of some new indomethacin analogs with a colon tumor cell growth inhibitory activity. Med Chem Res 26, 2205–2220 (2017). https://doi.org/10.1007/s00044-017-1932-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-017-1932-8

Keywords

Search

Navigation