Investigation of potential DNA damaging and apoptotic effects of PLK1 inhibitor SBE13 in breast cancer cell line MDA-MB-231

Polo-like kinase 1 (PLK1) regulates various steps of mitosis and aberrantly expressed in severaltumor types. As elevated levels of PLK1 contributes to tumorigenesis and poor prognosis,specific inhibition of PLK1 has garnered increasing attention in recent years in anticancerstudies. The objective of this study was to examine cytotoxic, apoptotic, and DNA-damagingpotentials of SBE13, a PLK1 inhibitor, against MDA-MB-231 breast cancer cells. Theregulatory efficacy of SBE13 on cell cycle arrest was also determined. Cytotoxicity of SBE13was assessed via XTT assay. Apoptosis, cell cycle distribution, and DNA damage responsewere also examined using the flow cytometry assay. The results revealed that SBE13 had adose-dependent cytotoxic effect in MDA-MB-231 cells. This compound has also induced cellcycle arrest at the G2/M point and significantly promoted apoptosis and DNA damage responsein MDA-MB-231 cells. Collectively, these data pointed out that SBE13 can be regarded as asuitable candidate for the therapy of breast cancer. However, further studies are required toconsolidate the anticancer activity of SBE13.

PDF

___

[1] Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2019, CA Cancer J Clin., 69(1) (2019) 7-34.
[2] Ergul M., Bakar-Ates F. RO3280: A Novel PLK1 Inhibitor, Suppressed the Proliferation of MCF-7 Breast Cancer Cells Through the Induction of Cell Cycle Arrest at G2/M Point, Anticancer Agents Med Chem., 19(15) (2019) 1846-1854.
[3] Howell A., Anderson A.S., Clarke R.B., Duffy S.W., Evans D.G., Garcia-Closas M., Gescher A.J., Key T.J., Saxton J.M., Harvie, M.N. Risk determination and prevention of breast cancer, Breast cancer research: BCR, 16(5) (2014) 446.
[4] Wu M., Wang Y., Yang D., Gong Y., Rao F., Liu R., Danna Y., Li J., Fan J., Chen J., Zhang W., Zhan, Q.A PLK1 kinase inhibitor enhances the chemosensitivity of cisplatin by inducing pyroptosis in oesophageal squamous cell carcinoma, EBioMedicine, 41 (2019) 244–255.
[5] de Cárcer G., Venkateswaran S. V., Salgueiro L., El Bakkali A., Somogyi K., Rowald K., Montañés, P., Sanclemente M., Escobar B., de Martino A., McGranahan N., Malumbres M., Sotillo, R. Plk1 overexpression induces chromosomal instability and suppresses tumor development, Nature communications, 9(1) (2018) 3012.
[6] Smith L., Farzan R., Ali S., Buluwela L., Saurin A. T., & Meek D.W. The responses of cancer cells to PLK1 inhibitors reveal a novel protective role for p53 in maintaining centrosome separation, Scientific reports, 7(1) (2017) 16115.
[7] Wang N.N., Li Z.H., Zhao H., Tao Y. F., Xu L. X., Lu J., Cao L., Du X. J., Sun L. C., Zhao W. L., Xiao P. F., Fang F., Su G. H., Li Y. H., Li G., Li Y. P., Xu Y. Y., Zhou H. T., Wu Y., Jin M. F., Pan J. Molecular targeting of the oncoprotein PLK1 in pediatric acute myeloid leukemia: RO3280, a novel PLK1 inhibitor, induces apoptosis in leukemia cells, International journal of molecular sciences, 16(1) (2015) 1266–1292.
[8] Choi M., Kim W., Cheon M. G., Lee C. W., & Kim J.E. Polo-like kinase 1 inhibitor BI2536 causes mitotic catastrophe following activation of the spindle assembly checkpoint in non-small cell lung cancer cells, Cancer letters, 357(2) (2015) 591–601.
[9] Keppner S., Proschak E., Schneider G., Spänkuch B. SBE13, a newly identified inhibitor of inactive polo-like kinase 1, J Cheminform. (2010) 2(Suppl 1) P54.
[10] Keppner S., Proschak E., Kaufmann M., Strebhardt K., Schneider G., & Spänkuch B. Biological impact of freezing Plk1 in its inactive conformation in cancer cells, Cell cycle, 9(4) (2010) 761–773.
[11] Keppner S., Proschak E., Schneider G., & Spänkuch B. Identification and validation of a potent type II inhibitor of inactive polo-like kinase 1, ChemMedChem, 4(11) (2009) 1806–1809.
[12] Lange L., Keppner-Witter S., Grigat J., & Spänkuch B. Combinatorial inhibition of Plk1 and PKCβ in cancer cells with different p53 status, Oncotarget, 5(8) (2014) 2263–2275.
[13] Gutteridge R. E., Ndiaye M. A., Liu X., & Ahmad N. Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics, Molecular cancer therapeutics, 15(7) (2016) 1427–1435.
[14] Dang S.C., Fan Y.Y., Cui L., Chen J.X., Qu J.G., Gu M. PLK1 as a potential prognostic marker of gastric cancer through MEK-ERK pathway on PDTX models, OncoTargets and therapy, 11 (2018) 6239–6247.
[15] Hikichi Y., Honda K., Hikami K., Miyashita H., Kaieda I., Murai S., Uchiyama N., Hasegawa M., Kawamoto T., Sato T., Ichikawa T., Cao S., Nie Z., Zhang L., Yang J., Kuida K., & Kupperman E. TAK-960, a novel, orally available, selective inhibitor of polo-like kinase 1, shows broadspectrum preclinical antitumor activity in multiple dosing regimens, Molecular cancer therapeutics, 11(3) (2012) 700–709.
[16] Tandle A.T., Kramp T., Kil W. J., Halthore A., Gehlhaus K., Shankavaram U., Tofilon P.J., Caplen N.J., & Camphausen K. Inhibition of pololike kinase 1 in glioblastoma multiforme induces mitotic catastrophe and enhances radiosensitisation, Albayrak G., Korkmaz F.D., Bali E.B., Bagriacik E.U., Antitumorigenic Effect of Memantine via Interfering Glutamate Metabolism in Mouse 4T1 Breast Tumor Model, Anticancer Agents Med Chem., (2020 European journal of cancer, 49(14) (2013) 3020–3028.