İrem ATLIHAN, Sevgi KOÇYİĞİT SEVİNÇ, Oya ORUN, Özgür YILMAZ, Şükriye Güniz KÜÇÜKGÜZEL, Pinar MEGA TİBER

Effect of flurbiprofen derivative (SGK597) on cell proliferation and apoptosis of breast cancer cell lines

Background and Aims: The incidence of breast cancer is increasing day by day, especially in women. The search for new drugs against breast cancer is the focus of attention in research. Breast cancer and prostate cancer have remarkable biological similarities. Therefore, the 4-(4-chlorophenyl)-3-(1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-5-((4-fluorobenzyl)thio)-4H- 1,2,4-triazole (SGK597) compound that is suppressing cell proliferation in prostate cancer, was studied in MCF-7 breast can- cer and MCF-10A mammary epithelial cell lines.Methods: The WST-8 method was used to determine cell viability and cytotoxicity of SGK597 in MCF-7 and MCF10-A cell lines. The JC-1 test was applied to determine changes in mitochondrial membrane potential. The protein expression levels of Bax, Bcl-2, and c-PARP associated with apoptosis were determined using Western blot analysis.Results: After 24 and 48 hours of incubation of SGK597, the IC50 values were 28.74 μM and 17.28 μM for MCF-7; 65.9 μM and 50.5 μM for MCF-10A, respectively. Mitochondrial membrane potential showed a tendency toward depolarization in MCF-7 cells as a result of increasing concentration of SGK597, while the same tendency was not seen for MCF-10A. As a result of western blot experiments, no increase in the Bax/Bcl-2 ratio and c-PARP expression level was observed, indicating no apoptosis.Conclusion: It was observed that the compound SGK597 suppressed MCF-7 cell proliferation. These results indicate that SGK597 may be a candidate compound for use as an anticancer agent.

Keywords:

Apoptosis, breast cancer, flurbiprofen, thioether, triazole,

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Ali, R., Mirza, Z., Ashraf, G. M., Kamal, M. A., Ansari, S. A., Daman- houri, G. A., … Sheikh, I. A. (2012). New anticancer agents: re- cent developments in tumor therapy. Anticancer Research, 32(7), 2999–3005.
Aydın, S., Kaushik-Basu, N., Arora, P., Basu, A., Nichols, D. B., Talele, T. T., … Küçükgüzel, Ş. G. (2013). Microwave assisted synthesis of some novel Flurbiprofen hydrazidehydrazones as anti-HCV NS5B and anticancer agents. Marmara Pharmaceutical Journal, 17, 26- 34.
Bakır, E., Çal, T., Aydın Dilsiz, S., Canpınar, H., Eken, A., & Ündeğer Bucurgat, Ü. (2021). Assessment of the cytotoxic, genotoxic, and apoptotic potential of flurbiprofen in HeLa and HepG2 cell lines. Journal of biochemical and molecular toxicology, 35(6), 1–11. https://doi.org/10.1002/jbt.22770
Becker S. (2015). A historic and scientific review of breast cancer: The next global healthcare challenge. International journal of gyn- aecology and obstetrics: the official organ of the International Feder- ation of Gynaecology and Obstetrics, 131 Suppl 1, S36–S39. https:// doi.org/10.1016/j.ijgo.2015.03.015
Birgül, K., Yıldırım, Y., Karasulu, H. Y., Karasulu, E., Uba, A. I., Yelekçi, K., … Küçükgüzel, Ş. G. (2020). Synthesis, molecular modeling, in vivo study and anticancer activity against prostate cancer of (+) (S)-naproxen derivatives. European journal of medicinal chemistry, 208, 112841. https://doi.org/10.1016/j.ejmech.2020.112841
Bradke, T. M., Hall, C., Carper, S. W., & Plopper, G. E. (2008). Phenyl- boronic acid selectively inhibits human prostate and breast can- cer cell migration and decreases viability. Cell adhesion & migra- tion, 2(3), 153–160. https://doi.org/10.4161/cam.2.3.6484
Çıkla, P., Tatar, E., Küçükgüzel, İ., Şahin, F., Yurdakul, D., Basu, A., … Küçükgüzel, Ş. G. (2013). Synthesis and characterization of flur- biprofen hydrazide derivatives as potential anti-HCV, anticancer and antimicrobial agents. Medicinal Chemistry Research, 22(12), 5685-5999. https://doi.org/10.1007/s00044-013-0550-3
Çıkla-Süzgün, P., & Küçükgüzel, Ş. G. (2021). Recent Progress on Apoptotic Activity of Triazoles. Current drug targets, 22(16), 1844– 1900. https://doi.org/10.2174/1389450122666210208181128
Çoruh, I., Çevik, Ö., Yelekçi, K., Djikic, T., & Küçükgüzel, Ş. G. (2018). Synthesis, anticancer activity, and molecular modeling of etodol- ac-thioether derivatives as potent methionine aminopeptidase (type II) inhibitors. Archiv der Pharmazie, 351(3-4), e1700195. https://doi.org/10.1002/ardp.201700195
Fröhlich, T., Mai, C., Bogautdinov, R. P., Morozkina, S. N., Shavva, A. G., Friedrich, O., … Tsogoeva, S. B. (2020). Synthesis of Tamox- ifen-Artemisinin and Estrogen-Artemisinin Hybrids Highly Po- tent Against Breast and Prostate Cancer. ChemMedChem, 15(15), 1473–1479. https://doi.org/10.1002/cmdc.202000174
Han, M. İ., & Küçükgüzel, Ş. G. (2022). Thioethers: An Overview. Current drug targets, 23(2), 170–219. https://doi.org/10.2174/1389450122666210614121237
Imai, M., Yokoe, H., Tsubuki, M., & Takahashi, N. (2019). Growth Inhibition of Human Breast and Prostate Cancer Cells by Cin- namic Acid Derivatives and Their Mechanism of Action. Bio- logical & pharmaceutical bulletin, 42(7), 1134–1139. https://doi. org/10.1248/bpb.b18-01002
King, Jr, J., & Khalili, K. (2001). Inhibition of human brain tumor cell growth by the anti-inflammatory drug, flurbiprofen. Oncogene, 20(47), 6864–6870. https://doi.org/10.1038/sj.onc.1204907
Küçükgüzel, Ş. G., & Çıkla-Süzgün, P. (2015). Recent advances bioactive 1,2,4-triazole-3-thiones. European journal of me- dicinal chemistry, 97, 830–870. https://doi.org/10.1016/j.ej- mech.2014.11.033
Liao, S., Umekita, Y., Guo, J., Kokontis, J. M., & Hiipakka, R. A. (1995). Growth inhibition and regression of human prostate and breast tumors in athymic mice by tea epigallocatechin gallate. Cancer let- ters, 96(2), 239–243. https://doi.org/10.1016/0304-3835(95)03948-v
Ly, J. D., Grubb, D. R., & Lawen, A. (2003). The mitochondrial mem- brane potential (deltapsi(m)) in apoptosis; an update. Apoptosis: an international journal on programmed cell death, 8(2), 115–128. https://doi.org/10.1023/a:1022945107762
McCormick, D. L., & Moon, R. C. (1983). Inhibition of mammary carcinogenesis by flurbiprofen, a non-steroidal antiinflamma- tory agent. British Journal of Cancer 48(6), 859–861. https://doi. org/10.1038/bjc.1983.278
Meegan, M. J., & O’Boyle, N. M. (2019). Special Issue “Anticancer Drugs”. Pharmaceuticals (Basel, Switzerland), 12(3), 134. https://doi. org/10.3390/ph12030134
Mega Tiber, P., Kocyigit Sevinc, S., Kilinc, O., & Orun, O. (2019). Biological effects of whole Z. officinale extract on chronic my- eloid leukemia cell line K562. Gene, 692, 217–222. https://doi. org/10.1016/j.gene.2019.01.015
Powles, T. J., Alexander, P., & Millar, J. L. (1978). Enhancement of anti-cancer activity of cytotoxic chemotherapy with protection of normal tissues by inhibition of P.G. synthesis. Biochemical Pharmacology, 27(9), 1389–1392. https://doi.org/10.1016/0006-2952(78)90127-2
Ren, Z.-J., Cao, D.-H., Zhang, Q., Ren, P.-W., Liu, L.-R., Wei, Q., … Dong, Q. (2019). First-degree family history of breast cancer is associated with prostate cancer risk: a systematic review and meta-analysis. BMC Cancer, 19(1), 871. https://doi.org/10.1186/ s12885-019-6055-9
Risbridger, G. P., Davis, I. D., Birrell, S. N., & Tilley, W. D. (2010). Breast and prostate cancer: more similar than different. Nature reviews. Cancer, 10(3), 205–212. https://doi.org/10.1038/nrc2795
Selvakumar, P., Lakshmikuttyamma, A., Das, U., Pati, H. N., Dim- mock, J. R., & Sharma, R. K. (2009). NC2213: a novel methionine aminopeptidase 2 inhibitor in human colon cancer HT29 cells. Molecular cancer, 8(65). https://doi.org/10.1186/1476-4598-8-65
Selvakumar, P., Lakshmikuttyamma, A., Dimmock, J. R., & Sharma, R. K. (2006). Methionine aminopeptidase 2 and cancer. Biochimica et biophysica acta, 1765(2), 148–154. https://doi.org/10.1016/j. bbcan.2005.11.001
Sun, Y. S., Zhao, Z., Yang, Z. N., Xu, F., Lu, H. J., Zhu, Z. Y., … Zhu, H. P. (2017). Risk Factors and Preventions of Breast Cancer. Interna- tional journal of biological sciences, 13(11), 1387–1397. https://doi. org/10.7150/ijbs.21635
Yamaoka, M., Yamamoto, T., Ikeyama, S., Sudo, K., & Fujita, T. (1993). Angiogenesis inhibitor TNP-470 (AGM-1470) potently inhibits the tumor growth of hormone-independent human breast and prostate carcinoma cell lines. Cancer research, 53(21), 5233–5236.
Yılmaz, Ö., Bayer, B., Bekçi, H., Uba, A. I., Cumaoğlu, A., Yelekçi, K., & Küçükgüzel, Ş. G. (2020). Synthesis, Anticancer Activity on Pros- tate Cancer Cell Lines and Molecular Modeling Studies of Flurbi- profen-Thioether Derivatives as Potential Target of MetAP (Type II). Medicinal chemistry, 16(6), 735–749. https://doi.org/10.2174/1 573406415666190613162322