BI2536, a potent and selective inhibitor of polo-like kinase 1, in combination with cisplatin exerts synergistic effects on gastric cancer cells

Lian,Guodong; Li,Leping; Shi,Yulong; Jing,Changqing; Liu,Jinglei; Guo,Xiaobo; Zhang,Qingqing; Dai,Tianyu; Ye,Fei; Wang,Yanyan; Chen,Man

doi:10.3892/ijo.2018.4255

BI2536, a potent and selective inhibitor of polo-like kinase 1, in combination with cisplatin exerts synergistic effects on gastric cancer cells

Authors:
- Guodong Lian
- Leping Li
- Yulong Shi
- Changqing Jing
- Jinglei Liu
- Xiaobo Guo
- Qingqing Zhang
- Tianyu Dai
- Fei Ye
- Yanyan Wang
- Man Chen
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Affiliations: Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China, Statistics and Medical Record Management Section, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China, Clinical Medical College of Jining Medical University, Jining, Shandong 272067, P.R. China, Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA, Biological Engineering School of Dalian Polytechnic University, Dalian, Liaoning 116034, P.R. China, Department of Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
Published online on: January 25, 2018 https://doi.org/10.3892/ijo.2018.4255
Pages: 804-814
Copyright: © Lian et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

BI2536 is a highly selective and potent inhibitor of polo-like kinase 1 (PLK1). In this study, we aimed to determine whether BI2536 and cisplatin can synergistically inhibit the malignant behavior of gastric cancer cells. For this purpose, the expression of PLK1 in gastric cancer cells was determined. The effects of BI2536, cisplatin, and the combination of BI2536 and cisplatin on gastric cancer cell viability, invasion, cell cycle arrest and apoptosis were assessed. Furthermore, the expression of cell cycle-regulated proteins was examined. Moreover, the differentially expressed proteins between the SGC-7901 and SGC-7901/DDP (cisplatin-resistant) cells, and the enriched signaling pathways were analyzed by protein pathway array following treatment with BI2536 (IC50) for 48 h. Our results revealed that PLK1 was upregulated in the SGC-7901/DDP (cisplatin-resistant) gastric cancer cells compared with the SGC-7901 cells. BI2536 enhanced the inhibitory effect of cisplatin on SGC-7901 cell viability and invasion. BI2536 induced G2/M arrest in SGC-7901 and SGC-7901/DDP cells. BI2536 promoted cisplatin-induced gastric cancer SGC-7901/DDP cell apoptosis. It also induced the differential expression of 68 proteins between the SGC-7901 and SGC-7901/DDP cells, and these differentially expressed proteins were involved in a number of cellular functions and signaling pathways, such as cell death, cell development, tumorigenesis, the cell cycle, DNA duplication/recombination/repair, cellular movement, and the Wnt/β-catenin and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK)/ribosomal S6 kinase 1 (RSK1) signaling pathways. On the whole, our findings suggest that BI2536 and cisplatin synergistically inhibit the malignant behavior of SGC-7901/DDP (cisplatin‑resistant) gastric cancer cells.

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1	de Martel C, Forman D and Plummer M: Gastric cancer: Epidemiology and risk factors. Gastroenterol Clin North Am. 42:219–240. 2013. View Article : Google Scholar : PubMed/NCBI
2	Daniyal M, Ahmad S, Ahmad M, Asif HM, Akram M, Ur Rehman S and Sultana S: Risk factors and epidemiology of gastric cancer in Pakistan. Asian Pac J Cancer Prev. 16:4821–4824. 2015. View Article : Google Scholar : PubMed/NCBI
3	Orditura M, Galizia G, Sforza V, Gambardella V, Fabozzi A, Laterza MM, Andreozzi F, Ventriglia J, Savastano B, Mabilia A, et al: Treatment of gastric cancer. World J Gastroenterol. 20:1635–1649. 2014. View Article : Google Scholar : PubMed/NCBI
4	Yasui W, Oue N, Ito R, Kuraoka K and Nakayama H: Search for new biomarkers of gastric cancer through serial analysis of gene expression and its clinical implications. Cancer Sci. 95:385–392. 2004. View Article : Google Scholar : PubMed/NCBI
5	Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V, et al: Arbeitsgemeinschaft Internistische Onkologie and EXPAND Investigators: Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): A randomised, open-label phase 3 trial. Lancet Oncol. 14:490–499. 2013. View Article : Google Scholar : PubMed/NCBI
6	Köhne CH, Wils JA and Wilke HJ: Developments in the treatment of gastric cancer in Europe. Oncology (Williston Park). 14(Suppl 14): 22–25. 2000.
7	Catalano V, Labianca R, Beretta GD, Gatta G, de Braud F and Van Cutsem E: Gastric cancer. Crit Rev Oncol Hematol. 71:127–164. 2009. View Article : Google Scholar : PubMed/NCBI
8	Tong W, Ye F, He L, Cui L, Cui M, Hu Y, Li W, Jiang J, Zhang DY and Suo J: Serum biomarker panels for diagnosis of gastric cancer. Onco Targets Ther. 9:2455–2463. 2016.PubMed/NCBI
9	Ngeow J, Tan IB and Choo SP: Targeted therapies in the treatment of gastric cancer. Asia Pac J Clin Oncol. 7:224–235. 2011. View Article : Google Scholar : PubMed/NCBI
10	Takai N, Hamanaka R, Yoshimatsu J and Miyakawa I: Polo-like kinases (Plks) and cancer. Oncogene. 24:287–291. 2005. View Article : Google Scholar : PubMed/NCBI
11	Chopra P, Sethi G, Dastidar SG and Ray A: Polo-like kinase inhibitors: An emerging opportunity for cancer therapeutics. Expert Opin Investig Drugs. 19:27–43. 2010. View Article : Google Scholar
12	Jang YJ, Kim YS and Kim WH: Oncogenic effect of Polo-like kinase 1 expression in human gastric carcinomas. Int J Oncol. 29:589–594. 2006.PubMed/NCBI
13	Zha X, Huang L, Yang M, Jingmin OU, Chen D and Fei Z: Study on folate deficiency and Polo-like kinase-1 (PLK-1) siRNA in synergistically inhibiting the growth of gastric carcinoma cell lines. Modern J Integrated Trad Chin Western Med. 24:917–920. 2015.
14	Otsu H, Iimori M, Ando K, Saeki H, Aishima S, Oda Y, Morita M, Matsuo K, Kitao H, Oki E, et al: Gastric cancer patients with high PLK1 expression and DNA aneuploidy correlate with poor prognosis. Oncology. 91:31–40. 2016. View Article : Google Scholar : PubMed/NCBI
15	Weiss L and Efferth T: Polo-like kinase 1 as target for cancer therapy. Exp Hematol Oncol. 1:382012. View Article : Google Scholar : PubMed/NCBI
16	Cholewa BD, Liu X and Ahmad N: The role of polo-like kinase 1 in carcinogenesis: Cause or consequence. Cancer Res. 73:6848–6855. 2013. View Article : Google Scholar : PubMed/NCBI
17	Mross K, Frost A, Steinbild S, Hedbom S, Rentschler J, Kaiser R, Rouyrre N, Trommeshauser D, Hoesl CE and Munzert G: Phase I dose escalation and pharmacokinetic study of BI 2536, a novel Polo-like kinase 1 inhibitor, in patients with advanced solid tumors. J Clin Oncol. 26:5511–5517. 2008. View Article : Google Scholar : PubMed/NCBI
18	Steegmaier M, Hoffmann M, Baum A, Lénárt P, Petronczki M, Krssák M, Gürtler U, Garin-Chesa P, Lieb S, Quant J, et al: BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol. 17:316–322. 2007. View Article : Google Scholar : PubMed/NCBI
19	Lénárt P, Petronczki M, Steegmaier M, Di Fiore B, Lipp JJ, Hoffmann M, Rettig WJ, Kraut N and Peters JM: The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1. Curr Biol. 17:304–315. 2007. View Article : Google Scholar : PubMed/NCBI
20	Chou T and Martin N: CompuSyn for drug combinations: PC software and user's guide: A computer program for quantitation of synergism and antagonism in drug combinations, and the determination of IC₅₀ and ED and LD NJ, 50 50 values. ComboSyn, Paramus. 2005.
21	Pace A, Savarese A, Picardo M, Maresca V, Pacetti U, Del Monte G, Biroccio A, Leonetti C, Jandolo B, Cognetti F, et al: Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. J Clin Oncol. 21:927–931. 2003. View Article : Google Scholar : PubMed/NCBI
22	Kawabe T: Kawabe. Mol Cancer Ther. 3:513–519. 2004.PubMed/NCBI
23	Anderson HJ, Andersen RJ and Roberge M: Inhibitors of the G2 DNA damage checkpoint and their potential for cancer therapy. Prog Cell Cycle Res. 5:423–430. 2003.PubMed/NCBI
24	Smits VA, Klompmaker R, Arnaud L, Rijksen G, Nigg EA and Medema RH: Polo-like kinase-1 is a target of the DNA damage checkpoint. Nat Cell Biol. 2:672–676. 2000. View Article : Google Scholar : PubMed/NCBI
25	van Vugt MA, Smits VA, Klompmaker R and Medema RH: Inhibition of Polo-like kinase-1 by DNA damage occurs in an ATM- or ATR-dependent fashion. J Biol Chem. 276:41656–41660. 2001. View Article : Google Scholar : PubMed/NCBI
26	van Vugt MA and Medema RH: Getting in and out of mitosis with Polo-like kinase-1. Oncogene. 24:2844–2859. 2005. View Article : Google Scholar : PubMed/NCBI
27	Kim SA, Kwon SM, Yoon JH and Ahn SG: The antitumor effect of PLK1 and HSF1 double knockdown on human oral carcinoma cells. Int J Oncol. 36:867–872. 2010.PubMed/NCBI
28	Jimeno A, Rubio-Viqueira B, Rajeshkumar V, Chan A, Solomon A and Hidalgo M: A fine-needle aspirate-based vulnerability assay identifies polo-like kinase 1 as a mediator of gemcitabine resistance in pancreatic cancer. Mol Cancer Ther. 9:311–318. 2010. View Article : Google Scholar : PubMed/NCBI
29	Wong N and Khan M: Abstract 4915: High degree of G2/M arrest induced by Polo-like kinase 1 (PLK1) inhibition is associated with radiosensitization. Cancer Res. 74:49152014. View Article : Google Scholar
30	Liu YF, Chen YJ and Chen CL: MS275 synergistically enhances the growth inhibitory effects of BI2536 in non-small-cell lung cancer cells. Pharm Biotechnol. 18:308–312. 2011.
31	Gleixner KV, Ferenc V, Gruze A, Kneidinger M, Baumgartner C, Mayerhofer M, et al: The Plk-1 Inhibitor BI 2536 Counteracts Proliferation and Viability of CML Cells and Synergizes with Imatinib and Nilotinib (AMN107) in Producing Growth Inhibition. Blood. 110:317A2007.
32	Mao J, Fan S, Ma W, Fan P, Wang B, Zhang J, Wang H, Tang B, Zhang Q, Yu X, et al: Roles of Wnt/β-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment. Cell Death Dis. 5:e10392014. View Article : Google Scholar
33	Shrivastava S, Kumar P, Jeengar MK and Naidu VG: T3038 - Inhibition of Wnt/β-catenin pathway by niclosamide: A therapeutic target for gastric cancer. National Institute of Pharmaceutical Education and Research (NIPER). 2014.
34	Nam HJ, Kim S, Lee MW, Lee BS, Hara T, Saya H, Cho H and Lee JH: The ERK-RSK1 activation by growth factors at G2 phase delays cell cycle progression and reduces mitotic aberrations. Cell Signal. 20:1349–1358. 2008. View Article : Google Scholar : PubMed/NCBI
35	Li R, Chen DF, Zhou R, Jia SN, Yang JS, Clegg JS and Yang WJ: Involvement of polo-like kinase 1 (Plk1) in mitotic arrest by inhibition of mitogen-activated protein kinase-extracellular signal-regulated kinase-ribosomal S6 kinase 1 (MEK-ERK-RSK1) cascade. J Biol Chem. 287:15923–15934. 2012. View Article : Google Scholar : PubMed/NCBI