Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Author(s): Mustafa Ergul* and Filiz Bakar-Ates

DOI: 10.2174/1871520619666190618162828

DownloadDownload PDF Flyer Cite As
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

Page: [1846 - 1854] Pages: 9

  • * (Excluding Mailing and Handling)

Abstract

Background: As a member of serine/threonine-protein kinase, Polo-like kinase 1 (PLK1) plays crucial roles during mitosis and also contributes to DNA damage response and repair. PLK1 is aberrantly expressed in many types of tumor cells and increased levels of PLK1 are closely related to tumorigenesis and poor clinical outcomes. Therefore, PLK1 is accepted as one of the potential targets for the discovery of novel anticancer agents. The objective of this study was to assess the cytotoxic effects of a novel PLK1 inhibitor, RO3280, against MCF-7, human breast cancer cells; HepG2, human hepatocellular carcinoma cells; and PC3, human prostate cancer cells, as well as non-cancerous L929 fibroblast cells.

Methods: Antiproliferative activity of RO3280 was examined using the XTT assay. Flow cytometry assay was performed to evaluate cell cycle distribution, apoptosis, multicaspase activity, mitochondrial membrane potential, and DNA damage response. Apoptosis with fluorescence imaging studies was also examined.

Results: According to the results of XTT assay, although RO3280 displayed potent cytotoxicity in all treated cancer cells, the most sensitive cell line was identified as MCF-7 cells that were selected for further studies. The compound induced a cell cycle arrest in MCF-7 cells at G2/M phase and significantly induced apoptosis, multicaspase activity, DNA damage response, and decreased mitochondrial membrane potential of MCF-7 cells.

Conclusion: Overall, RO3280 induces anticancer effects promoted mainly by DNA damage, cell cycle arrest, and apoptosis in breast cancer cells. Further studies are needed to assess its usability as an anticancer agent with specific cancer types.

Keywords: Apoptosis, DNA damage, cell cycle, cytotoxicity, PLK inhibition, RO3280.

Graphical Abstract

[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin., 2018, 68(1), 7-30.
[2]
Ruberte, A.C.; Plano, D.; Encío, I.; Aydillo, C.; Sharma, A.K.; Sanmartín, C. Novel selenadiazole derivatives as selective antitumor and radical scavenging agents. Eur. J. Med. Chem., 2018, 5(157), 14-27.
[3]
Liu, Z.; Sun, Q.; Wang, X. PLK1, a potential target for cancer therapy. Transl. Oncol., 2017, 10(1), 22-32.
[4]
Wang, Y.; Wu, L.; Yao, Y.; Lu, G.; Xu, L.; Zhou, J. Polo-like kinase 1 inhibitor BI 6727 induces DNA damage and exerts strong antitumor activity in small cell lung cancer. Cancer Lett., 2018, 436, 1-9.
[5]
Lee, J.K.; Ha, G.H.; Kim, H.S.; Lee, C.W. Oncogenic potential of BEX4 is conferred by Polo-like kinase 1-mediated phosphorylation. Exp. Mol. Med., 2018, 50(10), 138.
[6]
Chen, Z.; Chai, Y.; Zhao, T.; Li, P.; Zhao, L.; He, F.; Lang, Y.; Qin, J.; Ju, H. Effect of PLK1 inhibition on cisplatin-resistant gastric cancer cells. J. Cell. Physiol., 2018, 234(5), 5904-5914.
[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.; Liu, L.; Ni, J.; Wang, J.; Hu, S.Y.; Zhu, X.M.; Feng, X.; Pan, J. Molecular targeting of the oncoprotein PLK1 in pediatric acute myeloid leukemia: RO3280, a novel PLK1 inhibitor, induces apoptosis in leukemia cells. Int. J. Mol. Sci., 2015, 16(1), 1266-1292.
[8]
Noor, A.; Umelo, I.A.; Kronenberger, P.; Giron, P.; De Vlieghere, E.; De Wever, O.; Teugels, E.; De Grève, J. Targeting Polo-like kinase 1 and TRAIL enhances apoptosis in non-small cell lung cancer. Oncotarget, 2018, 9(47), 28731-28744.
[9]
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-ER K pathway on PDTX models. OncoTargets Ther., 2018, 11, 6239-6247.
[10]
Delacour, Q.; Gavet, O. Re-investigating PLK1 inhibitors as antimitotic agents. Mol. Cell. Oncol., 2017, 4(6)e1356430
[11]
Lian, G.; Li, L.; Shi, Y.; Jing, C.; Liu, J.; Guo, X.; Zhang, Q.; Dai, T.; Ye, F.; Wang, Y.; Chen, M. BI2536, a potent and selective inhibitor of polo-like kinase 1, in combination with cisplatin exerts synergistic effects on gastric cancer cells. Int. J. Oncol., 2018, 52(3), 804-814.
[12]
Ferrarotto, R.; Goonatilake, R.; Yoo, S.Y.; Tong, P.; Giri, U.; Peng, S.; Minna, J.; Girard, L.; Wang, Y.; Wang, L.; Li, L.; Diao, L.; Peng, D.H.; Gibbons, D.L.; Glisson, B.S.; Heymach, J.V.; Wang, J.; Byers, L.A.; Johnson, F.M. Epithelial-mesenchymal transition predicts polo-like kinase 1 inhibitor-mediated apoptosis in non-small cell lung cancer. Clin. Cancer Res., 2016, 22(7), 1674-1686.
[13]
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 broad-spectrum preclinical antitumor activity in multiple dosing regimens. Mol. Cancer Ther., 2012, 11(3), 700-709.
[14]
Valsasina, B.; Beria, I.; Alli, C.; Alzani, R.; Avanzi, N.; Ballinari, D.; Cappella, P.; Caruso, M.; Casolaro, A.; Ciavolella, A.; Cucchi, U.; De Ponti, A.; Felder, E.; Fiorentini, F.; Galvani, A.; Gianellini, L.M.; Giorgini, M.L.; Isacchi, A.; Lansen, J.; Pesenti, E.; Rizzi, S.; Rocchetti, M.; Sola, F. NMS-P937, an Orally Available, Specific Small-Molecule Polo-like Kinase 1 Inhibitor with Antitumor Activity in Solid and Hematologic Malignancies. Mol. Cancer Ther., 2012, 11(4), 1006-1016.
[15]
Oliveira, J.C.; Pezuk, J.A.; Brassesco, M.S.; Morales, A.G.; Queiroz, R.G.; Scrideli, C.A.; Tone, L.G. PLK1 expression and BI 2536 effects in childhood acute lymphoblastic leukemia. Pediatr. Blood Cancer, 2014, 61(7), 1227-1231.
[16]
Ikezoe, T.; Yang, J.; Nishioka, C.; Takezaki, Y.; Tasaka, T.; Togitani, K.; Koeffler, H.P.; Yokoyama, A. A novel treatment strategy targeting polo-like kinase 1 in hematological malignancies. Leukemia, 2009, 23(9), 1554-1576.
[17]
Chen, S.; Bartkovitz, D.; Cai, J.; Chen, Y.; Chen, Z.; Chu, X.J.; Le, K.; Le, N.T.; Luk, K.C.; Mischke, S.; Naderi-Oboodi, G.; Boylan, J.F.; Nevins, T.; Qing, W.; Chen, Y.; Wovkulich, P.M. Identification of novel, potent and selective inhibitors of Polo-like kinase 1. Bioorg. Med. Chem. Lett., 2012, 22(2), 1247-1250.
[18]
Goroshchuk, O.; Kolosenko, I.; Vidarsdottir, L.; Azimi, A.; Palm-Apergi, C. Polo-like kinases and acute leukemia. Oncogene, 2019, 38(1), 1-16.
[19]
He, Z.; Deng, W.; Jiang, B.; Liu, S.; Tang, M.; Liu, Y.; Zhang, J. Hsa-let-7b inhibits cell proliferation by targeting PLK1 in HCC. Gene, 2018, 673, 46-55.
[20]
Raab, M.; Sanhaji, M.; Matthess, Y.; Hörlin, A.; Lorenz, I.; Dötsch, C.; Habbe, N.; Waidmann, O.; Kurunci-Csacsko, E.; Firestein, R.; Becker, S.; Strebhardt, K. PLK1 has tumor-suppressive potential in APC-Truncated colon cancer cells. Nat. Commun., 2018, 9(1), 1-17.
[21]
Pajtler, K.W.; Sadowski, N.; Ackermann, S.; Althoff, K.; Schonbeck, K.; Batzke, K.; Schäfers, S.; Odersky, A.; Heukamp, L.; Astrahantseff, K.; Künkele, A.; Deubzer, H.E.; Schramm, A.; Sprüssel, A.; Thor, T.; Lindner, S.; Eggert, A.; Fischer, M.; Schulte, J.H. The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models. Oncotarget, 2017, 8(4), 6730-6741.
[22]
Tao, Y.F.; Li, Z.H.; Du, W.W.; Xu, L.X.; Ren, J.L.; Li, X.L.; Fang, F.; Xie, Y.; Li, M.; Qian, G.H.; Li, Y.H.; Li, Y.P.; Li, G.; Wu, Y.; Feng, X.; Wang, J.; He, W.Q.; Hu, S.Y.; Lu, J.; Pan, J. Inhibiting PLK1 induces autophagy of acute myeloid leukemia cells via mammalian target of rapamycin pathway dephosphorylation. Oncol. Rep., 2017, 37(3), 1419-1429.
[23]
Zhang, Z.; Zhang, G.; Kong, C. Targeted inhibition of Polo-like kinase 1 by a novel small-molecule inhibitor induces mitotic catastrophe and apoptosis in human bladder cancer cells. J. Cell. Mol. Med., 2017, 21(4), 758-767.
[24]
do Valle, Í.F.; Menichetti, G.; Simonetti, G.; Bruno, S.; Zironi, I.; Durso, D.F.; Mombach, J.C.M.; Martinelli, G.; Castellani, G.; Remondini, D. Network integration of multi-tumour omics data suggests novel targeting strategies. Nat. Commun., 2018, 9(1), 4514.
[25]
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, 2010, 9(4), 761-773.
[26]
Feng, Y.B.; Lin, D.C.; Shi, Z.Z.; Wang, X.C.; Shen, X.M.; Zhang, Y.; Du, X.L.; Luo, M.L.; Xu, X.; Han, Y.L.; Cai, Y.; Zhang, Z.Q.; Zhan, Q.M.; Wang, M.R. Overexpression of PLK1 is associated with poor survival by inhibiting apoptosis via enhancement of survivin level in esophageal squamous cell carcinoma. Int. J. Cancer, 2009, 124(3), 578-588.
[27]
Li, J.; Wang, R.; Kong, Y.; Broman, M.M.; Carlock, C.; Chen, L.; Li, Z.; Farah, E.; Ratliff, T.L.; Liu, X. Targeting Plk1 to enhance efficacy of olaparib in castration-resistant prostate cancer. Mol. Cancer Ther., 2017, 16(3), 469-479.
[28]
Roos, W.P.; Kaina, B. DNA damage-induced cell death by apoptosis. Trends Mol. Med., 2006, 12(9), 440-450.
[29]
Driscoll, D.L.; Chakravarty, A.; Bowman, D.; Shinde, V.; Lasky, K.; Shi, J.; Vos, T.; Stringer, B.; Amidon, B.; D’Amore, N.; Hyer, M.L. Plk1 inhibition causes post-mitotic DNA damage and senescence in a range of human tumor cell lines. PLoS One, 2014, 9(11)e111060