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

Yıl 2021, Cilt: 51 Sayı: 2, 161 - 166, 31.08.2021

Gökçe Cihan-üstündağ Berna Somuncu Meltem Müftüoğlu Nilgün Karalı

Öz

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, 1H-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.

Anahtar Kelimeler

indomethacin, acemetacin, tromethamine, HCT116, anti-cancer

Destekleyen Kurum

The Scientific and Technological Research Council of Turkey (TUBITAK)

Proje Numarası

212T026 and 215S614

Kaynakça

• • 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 Journal of Pharmaceutics and Biopharmaceutics, 131, 109-119. http:// dx.doi.org/10.1016/j.ejpb.2018.08.001.
• • Chávez-Piña, A. E., McKnight, W., Dicay, M., Castañeda-Hernández, G., & Wallace, J. L. (2007). Mechanisms underlying the antiinflammatory activity and gastric safety of acemetacin. British Journal of Pharmacology, 152, 930-938. http://dx.doi.org/10.1038/ sj.bjp.0707451.
• • Cheng, Y. L., Zhang, G. Y., Li, C., & Lin, J. (2013). Screening for novel protein targets of indomethacin in HCT116 human colon cancer cells using proteomics. Oncology Letters, 6, 1222-1228. http:// dx.doi.org/10.3892/ol.2013.1560.
• • Curry, J. M., Besmer, D. M., Erick, T. K., Steuerwald, N., Das Roy, L., Grover, 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.
• • Ettarh, R., Cullen, A., & Calamai, A. (2010). NSAIDs and cell proliferation in colorectal cancer. Pharmaceuticals, 3, 2007-2021. http:// dx.doi.org/10.3390/ph3072007.
• • 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.
• • Gołab, J., Kozar, K., Kamiński, R., Czajka, A., Marczak, M., Świtaj, T. … Jakóbisiak, 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.
• • Hawcroft, G., Gardner, S. H., & Hull, M. A. (2003). Activation of peroxisome proliferator-activated receptor γ 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.
• • 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.
• • 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.
• • Kahan, A. (1985). Watersoluble derivatives of non-steroidal antiinflammatory agents and a process for the production thereof. US Patent 4,518,608.
• • Kisara, S., Maekawa, I., Sasaki, K., Suzuki, N., Hayashi, A., Furusawa, 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 Pharmacology, 81, 247-250.
• • Lu, X., Xie, W., Reed, D., Bradshaw, W. S., & Simmons, D. L. (1995). Nonsteroidal antiinflammatory drugs cause apoptosis and induce 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 esophageal 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.
• • Real-Time and Dynamic Monitoring of Cell Proliferation and Viability for Adherent Cells. xCelligence System Application Note No. 1. (2013, January). Retrieved from http://www.aceabio.com/ wp-content/uploads/Monitoring-Cell-Proliferation-and-Viabilityfor- Adherent-Cells.pdf.
• • 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.
• • 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 toxicology, 34(2), e22433. https://doi.org/10.1002/jbt.22433.
• • Serajuddin, A. T. (2007). Salt formation to improve drug solubility. Advanced Drug Delivery Reviews, 59, 603-616. http://dx.doi. org/10.1016/j.addr.2007.05.010.
• • Smith, M. L., Hawcroft, G., & Hull, M. A. (2000). The effect of nonsteroidal 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.
• • Tavares, I. A., & Bennett, A. (1993). Acemetacin and indomethacin: differential inhibition of constitutive and inducible cyclo-oxygenases in human gastric mucosa and leucocytes. International Journal of Tissue Reactions, 15, 49-53.
• • 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.
• • Waddell, W. R., Gerner, R. E., & Reich, M. P. (1983). Nonsteroid antiinflammatory drugs and tamoxifen for desmoid tumors and carcinoma of the stomach. Journal of Surgical Oncology, 22, 197-211. http://dx.doi.org/10.1002/jso.2930220314.
• • Xu, M. H., & Zhang, G. Y. (2005). Effect of indomethacin on cell cycle proteins in colon cancer cell lines. World Journal of Gastroenterology, 11, 1693-1696. http://dx.doi.org/10.3748/wjg.v11.i11.1693.
• • Zhou, D., Papayannis, I., Mackenzie, G. G., Alston, N., Ouyang, N., Huang, L. … Rigas, B. (2013). The anticancer effect of phosphotyrosol- indomethacin (MPI-621), a novel phosphoderivative of indomethacin: In vitro and in vivo studies. Carcinogenesis, 34, 943- 951. http://dx.doi.org/10.1093/carcin/bgs394.