Research Article


DOI :10.26650/IstanbulJPharm.2021.876788   IUP :10.26650/IstanbulJPharm.2021.876788    Full Text (PDF)

Anti-proliferative effects of indomethacin, acemetacin and their tromethamine salts in HCT116 human colon cancer cells

Gökçe Cihan ÜstündağBerna SomuncuMeltem MüftüoğluNilgün Lütfiye Karalı

Background and Aims: Since 1980's, several preclinical studies have been published on the anti-colorectal cancer activity of the nonsteroidal anti-inflammatory drug indomethacin. The direct anti-proliferative effect of indomethacin seems to occur via a variety of reported COX-independent mechanisms. Acemetacin is a glycolic acid ester derivative of indomethacin and contrary to indomethacin, there is not much published research on anti-cancer effects of acemetacin. Herein, we compared the in vitro anti-proliferative properties of indomethacin, acemetacin, and their tromethamine salts in HCT116 colon cancer cells. Methods: The tromethamine salts of indomethacin and acemetacin were synthesized and the structures were established by microanalysis, IR, 1 H-NMR, 13C-NMR (APT) and 2D-NMR (HSQC and HMBC) spectrometry. Cell proliferation assays were performed using xCELLigence real-time cell analysis system. Results: Indomethacin exhibited profound inhibitory effects with IC50 values at low micromolar ranges. Acemetacin exhibited far lower cytotoxic activity as compared to that of indomethacin. Surprisingly, indomethacin-tromethamine salt was 2-fold and 4.4-fold more potent than indomethacin at 48 and 72 h, respectively, while maintaining its activity at 24 h. The tromethamine salt of acemetacin was more potent than acemetacin at 24 h and 48 h post-treatment. Conclusion: The anti-proliferative effect of indomethacin in HCT116 cells was found to be at low micro-molar levels. The esterification of indomethacin with glycolic acid caused a strong decrease in anti-proliferative effect. The salt formation caused a positive effect on the anti-proliferative activity of indomethacin and indomethacin-tromethamine salt may be a promising candidate for additional in vivo studies.


PDF View

References

  • Bookwala, M., Thipsay, P., Ross, S., Zhang, F., Bandari, S., & Repka, M. A. (2018). Preparation of a crystalline salt of indomethacin and tromethamine by hot melt extrusion technology. European Jour-nal of Pharmaceutics and Biopharmaceutics, 131, 109-119. http:// dx.doi.org/10.1016/j.ejpb.2018.08.001. google scholar
  • Châvez-Pina, A. E., McKnight, W., Dicay, M., Castaneda-Hernân-dez, G., & Wallace, J. L. (2007). Mechanisms underlying the anti-inflammatory activity and gastric safety of acemetacin. British Journal of Pharmacology, 152, 930-938. http://dx.doi.org/10.1038/ sj.bjp.0707451. google scholar
  • Cheng, Y. L., Zhang, G. Y., Li, C., & Lin, J. (2013). Screening for novel protein targets of indomethacin in HCT116 human colon can-cer cells using proteomics. Oncology Letters, 6, 1222-1228. http:// dx.doi.org/10.3892/ol.2013.1560. google scholar
  • Curry, J. M., Besmer, D. M., Erick, T. K., Steuerwald, N., Das Roy, L., Gro-ver, P., Rao, S., Nath, S., Ferrier J. W., Reid, R. W. & Mukherjee, P. (2019). Indomethacin enhances anti-tumor efficacy of a MUC1 peptide vaccine against breast cancer in MUC1 transgenic mice. PLoS ONE, 14(11), e0224309. https://doi.org/10.1371/journal.pone.0224309. google scholar
  • Ettarh, R., Cullen, A., & Calamai, A. (2010). NSAIDs and cell prolif-eration in colorectal cancer. Pharmaceuticals, 3, 2007-2021. http:// dx.doi.org/10.3390/ph3072007. google scholar
  • Giardina, C., & Inan, M. S. (1998). Nonsteroidal anti-inflammatory drugs, short-chain fatty acids, and reactive oxygen metabolism in human colorectal cancer cells. Biochimica et Biophysica Acta, 1401, 277-288. http://dx.doi.org/10.1016/s0167-4889(97)00140-7. google scholar
  • Gotab, J., Kozar, K., Kaminski, R., Czajka, A., Marczak, M., Switaj, T. ... Jaköbisiak, K. M. (2000). Interleukin 12 and indomethacin exert a synergistic, angiogenesis-dependent antitumor activity in mice. Life Sciences, 66, 1223-1230. http://dx.doi.org/10.1016/s0024-3205(00)00427-6. google scholar
  • Hawcroft, G., Gardner, S. H., & Hull, M. A. (2003). Activation of per-oxisome proliferator-activated receptor y does not explain the antiproliferative activity of the nonsteroidal anti-inflammatory drug indomethacin on human colorectal cancer cells. Journal of Pharmacology and Experimental Therapeutics, 305, 632-637. http://dx.doi.org/10.1124/jpet.103.048769. google scholar
  • Hull, M. A., Gardner, S. H., & Hawcroft, G. (2003). Activity of the non-steroidal anti-inflammatory drug indomethacin against colorectal cancer. Cancer Treatment Reviews, 29, 309-320. http:// dx.doi.org/10.1016/S0305-7372(03)00014-8. google scholar
  • Jana, N. R. (2008). NSAIDs and apoptosis. Cellular and Molecular Life Sciences, 65, 1295-1301. http://dx.doi.org/10.1007/s00018-008-7511-x. google scholar
  • Kahan, A. (1985). Watersoluble derivatives of non-steroidal anti-inflammatory agents and a process for the production thereof. US Patent 4,518,608. google scholar
  • Kisara, S., Maekawa, I., Sasaki, K., Suzuki, N., Hayashi, A., Furu-sawa, S., Takayanagi, Y., & Sasaki, K. (1993). Antitumor activity of acemetacin in mice bearing colon 26 carcinoma: a preliminary report. Research Communications in Chemical Pathology and Phar-macology, 81, 247-250. google scholar
  • Lu, X., Xie, W., Reed, D., Bradshaw, W. S., & Simmons, D. L. (1995). Nonsteroidal antiinflammatory drugs cause apoptosis and in-duce cyclooxygenases in chicken embryo fibroblasts. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 92, 7961-7965. http://dx.doi.org/10.1073/pnas.92.17.7961. Qin, S., Xu, C., Li, S., Yang, C., Sun, X., Wang, X., Tang, S. C., & Ren, H. (2015). Indomethacin induces apoptosis in the EC109 esopha-geal cancer cell line by releasing second mitochondria-derived activator of caspase and activating caspase-3. Molecular medicine reports, 11, 4694-4700. https://doi.org/10.3892/mmr.2015.3331. google scholar
  • Real-Time and Dynamic Monitoring of Cell Proliferation and Vi-ability for Adherent Cells. xCelligence System Application Note No. 1. (2013, January). Retrieved from http://www.aceabio.com/ wp-content/uploads/Monitoring-Cell-Proliferation-and-Viability-for-Adherent-Cells.pdf. google scholar
  • Saal, C., & Becker, A. (2013). Pharmaceutical salts: a summary on doses of salt formers from the Orange Book. European Journal of Pharmaceutical Sciences, 49, 614-623. http://dx.doi.org/10.1016/j. ejps.2013.05.026. google scholar
  • Seetha, A., Devaraj, H., & Sudhandiran, G. (2020). Indomethacin and juglone inhibit inflammatory molecules to induce apoptosis in colon cancer cells. Journal of biochemical and molecular toxicol-ogy, 34(2), e22433. https://doi.org/10.1002/jbt.22433. google scholar
  • Serajuddin, A. T. (2007). Salt formation to improve drug solubil-ity. Advanced Drug Delivery Reviews, 59, 603-616. http://dx.doi. org/10.1016/j.addr.2007.05.010. google scholar
  • Smith, M. L., Hawcroft, G., & Hull, M. A. (2000). The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells: evidence of different mechanisms of action. European Journal of Cancer, 36, 664-674. http://dx.doi.org/10.1016/s0959-8049(99)00333-0. google scholar
  • Tavares, I. A., & Bennett, A. (1993). Acemetacin and indomethacin: differential inhibition of constitutive and inducible cyclo-oxygen-ases in human gastric mucosa and leucocytes. International Jour-nal of Tissue Reactions, 15, 49-53. google scholar
  • Waddell, W. R., & Gerner, R. E. (1980). Indomethacin and ascorbate inhibit desmoid tumors. Journal of Surgical Oncology, 15, 85-90. http://dx.doi.org/10.1002/jso.2930150113. google scholar
  • Waddell, W. R., Gerner, R. E., & Reich, M. P. (1983). Nonsteroid anti-inflammatory drugs and tamoxifen for desmoid tumors and car-cinoma of the stomach. Journal of Surgical Oncology, 22, 197-211. http://dx.doi.org/10.1002/jso.2930220314. google scholar
  • Xu, M. H., & Zhang, G. Y. (2005). Effect of indomethacin on cell cycle proteins in colon cancer cell lines. World Journal of Gastroenterol-ogy, 11, 1693-1696. http://dx.doi.org/10.3748/wjg.v11.i11.1693. google scholar
  • Zhou, D., Papayannis, I., Mackenzie, G. G., Alston, N., Ouyang, N., Huang, L. ... Rigas, B. (2013). The anticancer effect of phospho-tyrosol-indomethacin (MPI-621), a novel phosphoderivative of indomethacin: In vitro and in vivo studies. Carcinogenesis, 34, 943951. http://dx.doi.org/10.1093/carcin/bgs394. google scholar

Citations

Copy and paste a formatted citation or use one of the options to export in your chosen format


EXPORT



APA

Cihan Üstündağ, G., Somuncu, B., Müftüoğlu, M., & Karalı, N.L. (2021). Anti-proliferative effects of indomethacin, acemetacin and their tromethamine salts in HCT116 human colon cancer cells. İstanbul Journal of Pharmacy, 51(2), 161-166. https://doi.org/10.26650/IstanbulJPharm.2021.876788


AMA

Cihan Üstündağ G, Somuncu B, Müftüoğlu M, Karalı N L. Anti-proliferative effects of indomethacin, acemetacin and their tromethamine salts in HCT116 human colon cancer cells. İstanbul Journal of Pharmacy. 2021;51(2):161-166. https://doi.org/10.26650/IstanbulJPharm.2021.876788


ABNT

Cihan Üstündağ, G.; Somuncu, B.; Müftüoğlu, M.; Karalı, N.L. Anti-proliferative effects of indomethacin, acemetacin and their tromethamine salts in HCT116 human colon cancer cells. İstanbul Journal of Pharmacy, [Publisher Location], v. 51, n. 2, p. 161-166, 2021.


Chicago: Author-Date Style

Cihan Üstündağ, Gökçe, and Berna Somuncu and Meltem Müftüoğlu and Nilgün Lütfiye Karalı. 2021. “Anti-proliferative effects of indomethacin, acemetacin and their tromethamine salts in HCT116 human colon cancer cells.” İstanbul Journal of Pharmacy 51, no. 2: 161-166. https://doi.org/10.26650/IstanbulJPharm.2021.876788


Chicago: Humanities Style

Cihan Üstündağ, Gökçe, and Berna Somuncu and Meltem Müftüoğlu and Nilgün Lütfiye Karalı. Anti-proliferative effects of indomethacin, acemetacin and their tromethamine salts in HCT116 human colon cancer cells.” İstanbul Journal of Pharmacy 51, no. 2 (Sep. 2021): 161-166. https://doi.org/10.26650/IstanbulJPharm.2021.876788


Harvard: Australian Style

Cihan Üstündağ, G & Somuncu, B & Müftüoğlu, M & Karalı, NL 2021, 'Anti-proliferative effects of indomethacin, acemetacin and their tromethamine salts in HCT116 human colon cancer cells', İstanbul Journal of Pharmacy, vol. 51, no. 2, pp. 161-166, viewed 24 Sep. 2021, https://doi.org/10.26650/IstanbulJPharm.2021.876788


Harvard: Author-Date Style

Cihan Üstündağ, G. and Somuncu, B. and Müftüoğlu, M. and Karalı, N.L. (2021) ‘Anti-proliferative effects of indomethacin, acemetacin and their tromethamine salts in HCT116 human colon cancer cells’, İstanbul Journal of Pharmacy, 51(2), pp. 161-166. https://doi.org/10.26650/IstanbulJPharm.2021.876788 (24 Sep. 2021).


MLA

Cihan Üstündağ, Gökçe, and Berna Somuncu and Meltem Müftüoğlu and Nilgün Lütfiye Karalı. Anti-proliferative effects of indomethacin, acemetacin and their tromethamine salts in HCT116 human colon cancer cells.” İstanbul Journal of Pharmacy, vol. 51, no. 2, 2021, pp. 161-166. [Database Container], https://doi.org/10.26650/IstanbulJPharm.2021.876788


Vancouver

Cihan Üstündağ G, Somuncu B, Müftüoğlu M, Karalı NL. Anti-proliferative effects of indomethacin, acemetacin and their tromethamine salts in HCT116 human colon cancer cells. İstanbul Journal of Pharmacy [Internet]. 24 Sep. 2021 [cited 24 Sep. 2021];51(2):161-166. Available from: https://doi.org/10.26650/IstanbulJPharm.2021.876788 doi: 10.26650/IstanbulJPharm.2021.876788


ISNAD

Cihan Üstündağ, Gökçe - Somuncu, Berna - Müftüoğlu, Meltem - Karalı, NilgünLütfiye. Anti-proliferative effects of indomethacin, acemetacin and their tromethamine salts in HCT116 human colon cancer cells”. İstanbul Journal of Pharmacy 51/2 (Sep. 2021): 161-166. https://doi.org/10.26650/IstanbulJPharm.2021.876788



TIMELINE


Submitted08.02.2021
Accepted14.05.2021
Published Online31.08.2021

LICENCE


Attribution-NonCommercial (CC BY-NC)

This license lets others remix, tweak, and build upon your work non-commercially, and although their new works must also acknowledge you and be non-commercial, they don’t have to license their derivative works on the same terms.


SHARE




Istanbul University Press aims to contribute to the dissemination of ever growing scientific knowledge through publication of high quality scientific journals and books in accordance with the international publishing standards and ethics. Istanbul University Press follows an open access, non-commercial, scholarly publishing.