A PLK1 inhibitor, RO3280, suppresses proliferation of SNU-16 gastric cancer cells via apoptosis
DOI:
https://doi.org/10.3329/bjp.v19i2.71704Keywords:
Anti-cancer, Apoptosis, DNA demage, PLK1 inhibition, RO3280, XTT assayAbstract
This study examines the anti-tumor, pro-apoptotic, and genotoxic effects of polo-like kinase 1 (PLK1) inhibitor RO3280 on the gastric cancer cell line SNU-16. Using the XTT assay, the antiproliferative effect of the compound was identified and showed a significant antiproliferative effect (p<0.01) with the IC50 value of 9.64 µM for 24 hours. RO3280 considerably enhanced the expression of Bax and cleaved caspase-3 (p<0.01) and dramatically lowered the BCL-2 level (p<0.01), demonstrating an apoptotic effect. It greatly raised the expression of 8-oxo-dG, a DNA damage marker, and cleaved PARP, a degraded version of the PARP enzyme involved in DNA repair (p<0.05 and p<0.01, respectively). In addition, flow cytometric studies for annexin V and caspase-3/7 revealed that RO3280 markedly improved the apoptotic cell profile (p<0.01). It reduced the mitochondrial membrane potential and DNA damage (p<0.01). These findings suggest that RO3280 has an antitumor impact by damaging DNA and inducing apoptosis in SNU-16 gastric cancer cells.
Downloads
252
268
References
Andree HAM, Reutelingsperger CPM, Hauptmann R, Hemker HC, Hermens WT, Willems GM. Binding of vascular anti-coagulant α (VACα) to planar phospholipid bilayers. J Biol Chem. 1990; 265: 4923-28.
Archambault V, Glover DM. Polo-like kinases: Conservation and divergence in their functions and regulation. Nat Rev Mol Cell Biol. 2009; 10: 265-75.
Ataseven D, Tastemur S, Yulak F, Karabulut S, Ergul M. GSK461364A suppresses proliferation of gastric cancer cells and induces apoptosis. Toxicol in Vitro. 2023; 90: 105610.
Baig S, Seevasant I, Mohamad J, Mukheem A, Huri HZ, Kamarul T. Potential of apoptotic pathway-targeted cancer therapeutic research: Where do we stand? Cell Death Dis. 2016; 7: e2058.
Bakar-Ates F, Ozkan E, Sengel-Turk CT. Encapsulation of cucurbitacin B into lipid polymer hybrid nanocarriers induced apoptosis of MDAMB231 cells through PARP cleavage. Intern J Pharm. 2020; 586: 119565.
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, ShenL, Sawaki A, Kang YK. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 2010; 376: 687-97.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, TorreLA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 coun-tries. CA Canc J Clinic. 2018; 68: 394-424.
BruinsmaW, Raaijmakers JA, Medema RH. Switching polo-like kinase-1 on and off in time and space. Trends Biochem Sci. 2012; 37: 534-42.
Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol. 2020; 17: 395-417.
Cavalcante GC, Schaan AP, Cabral GF, Santana-Da-Silva MN, Pinto P, Vidal AF, Ribeiro-Dos-Santos A. A cell’s fate: An overview of the molecular biology and genetics of apoptosis. Int J Mol Sci. 2019; 20: 1-20.
Chen XH, Lan B, Qu Y, Zhang XQ, Cai Q, Liu BY, Zhu ZG. Inhibitory effect of polo-like kinase 1 depletion on mitosis and apoptosis of gastric cancer cells. World J Gastroenterol. 2006; 12: 29-35.
Chen Z, ChaiY, Zhao T, Li P, Zhao L, He F, Ju H. Effect of PLK1 inhibition on cisplatin-resistant gastric cancer cells. J Cell Physiol. 2019; 234: 5904-14.
Chilamakuri R, Rouse DC, Agarwal S. Inhibition of polo-like kinase 1 by HMN-214 blocks cell cycle progression and ınhibits neuroblastoma growth. Pharmaceuticals (Basel) 2022; 15: 523.
Eckerdt F, Yuan J, Strebhardt K. Polo-like kinases and oncogenesis. Oncogene 2005; 24: 267-76.
Ergul M, Bakar-Ates F. A specific inhibitor of polo-like kinase 1, GSK461364A, suppresses proliferation of Raji Burkitt’s lymphoma cells through mediating cell cycle arrest, DNA damage, and apoptosis. Chem-Biol Interact. 2020; 332: 109288.
Ergul M, Bakar-Ates F. RO3280: A novel PLK1 ınhibitor, suppressed the proliferation of MCF-7 breast cancer cells through the ınduction of cell cycle arrest at G2/M point. Anticancer Agents Med Chem. 2019; 19: 1846-54.
ErgulM, Bakar-Ates F. Investigation of molecular mechanisms underlying the antiproliferative effects of colchicine against PC3 prostate cancer cells. Toxicol in Vitro. 2021; 73: 105138.
Filiz AK, Joha Z, Yulak F. Mechanism of anti-cancer effect of beta-glucan on SH-SY5Y cell line. Bangladesh J Pharmacol. 2021; 16: 122-28.
Finkel E. The mitochondrion: Is it central to apoptosis? Science 2001; 292: 624-26.
Gheghiani L, Shang S, Fu Z. Targeting the PLK1-FOXO1 pathway as a novel therapeutic approach for treating advanced prostate cancer. Sci Rep. 2020; 10: 12327.
Guo Q, Zhang H, Deng Y, Zhai S, Jiang Z, Zhu D, Wang L. Ligand- and structural-based discovery of potential small molecules that target the colchicine site of tubulin for cancer treatment. Eur J Med Chem. 2020; 196: 112328.
Hearps AC, Burrows J, Connor CE, Woods GM, Lowenthal RM, Ragg SJ. Mitochondrial cytochrome c release precedes transmembrane depolarisation and caspase-3 activation during ceramide-induced apoptosis of Jurkat T cells. Apoptosis 2002; 7: 387-94.
Jan R, Chaudhry GS. Understanding apoptosis and apoptotic pathways targeted cancer therapeutics. Adv Pharm Bull. 2019; 9: 205-18.
Joha, Z, Ozturk A., YulakF, Karatas O, Ataseven H. Mecha-nism of anticancer effect of gambogic acid on gastric signet ring cell carcinoma. Med Oncol. 2023; 40: 1-8.
Kang YK, Yook JH, ParkYK, Lee JS, Kim YW, Kim JY, Noh SH. PRODIGY: A phase III study of neoadjuvant docetaxel, oxaliplatin, and S-1 plus surgery and adjuvant s-1 versus surgery and adjuvant s-1 for resectable advanced gastric cancer. J Clin Oncol. 2021; 39: 2903-13.
Kerr JF, Wyllie AH, Curri AR. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972; 26: 239-57.
Krysko DV, Roels F, Leybaert L, D’Herde K. Mitochondrial transmembrane potential changes support the concept of mitochondrial heterogeneity during apoptosis. J Histochem Cytochem. 2001; 49: 1277-84.
Lee S, Jeong YJ, Yu A, Kwak HJ, Cha J, Kang I. Carfilzomib enhances cisplatin-induced apoptosis in SK-N- BE (2)-M17 human neuroblastoma cells. Sci Rep. 2019; 9: 1-14.
Li J, Wang R, Schweickert PG, Karki A, Yang Y, Kong Y, Liu X. Plk1 inhibition enhances the efficacy of gemcitabine in human pancreatic cancer. Cell Cycle. 2016; 15: 711-19.
Ly JD, Grubb DR, Lawen A. The mitochondrial membrane potential (deltapsi(m)) in apoptosis: An update. Apoptosis 2003; 8: 115-28.
Majno G, Joris I. Apoptosis, oncosis, and necrosis. An over-view of cell death. Am J Pathol. 1995; 146: 3-15.
Ng WTW, Shin JS, Roberts TL, WangB, Lee CS. Molecular interactions of polo-like kinase 1 in human cancers. J Clin Pathol. 2016; 69: 557-62.
Otto T, Sicinski P. Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer. 2017; 17: 93-115.
Pajtler KW, Sadowski N, Ackermann S, Althoff K, Schönbeck K, Batzke K, Schulte JH. The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models. Oncotarget 2017; 8: 6730-41.
Petronczki M, Lenart P, Peters JM. Polo on the rise-from mito-tic entry to cytokinesis with Plk1. Dev Cell. 2008; 14: 646-59.
Porter AG, Jänicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 1999; 6: 99-104.
Riedl SJ, Shi Y. Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol. 2004; 5: 897-907.
Rudin CM, Thompson CB. Apoptosis and disease: Regulation and clinical relevance of programmed cell death. Annu Rev Med. 1997; 48: 267-81.
Sachdev E, Tabatabai R, Roy V, Rimel BJ, Mita MM. PARP ınhibition in cancer: An update on clinical development. Targ Oncol. 2019; 14: 657-79.
Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet 2020; 396: 635-48.
Song R, Hou G, Yang J, Yuan J, Wang C, Chai T, Liu Z. Effects of PLK1 on proliferation, invasion and metastasis of gastric cancer cells through epithelial-mesenchymal transition. Oncol Lett. 2018; 16: 5739-44.
Tait JF, Gibson D, Fujikawa K. Phospholipid binding properties of human placental anticoagulant protein-I, a member of the lipocortin family. J Biol Chem. 1989; 264: 7944-49.
Takaki T, Trenz K, Costanzo V, Petronczki M. Polo-like kinase 1 reaches beyond mitosis: Cytokinesis, DNA damage response, and development. Curr Opin Cell Biol. 2008; 20: 650-60.
Tang H, Zhang Y, Li D, Fu S, Tang M, Wan L, Chen L. Discovery and synthesis of novel magnolol derivatives with potent anti-cancer activity in non-small cell lung cancer. Eur J Med Chem. 2018; 156: 190-205.
Tao YF, Li ZH, DuWW, Xu LX, Ren JL, Li XL, Pan J. Inhibiting PLK1 induces autophagy of acute myeloid leukemia cells via mammalian target of rapamycin pathway dephosphorylation. Oncol Rep. 2017; 37: 1419-29.
Ueda A, Oikawa K, Fujita K, Ishikawa A, Sato E, Ishikawa T, Kanekura K.Therapeutic potential of PLK1 inhibition in triple-negative breast cancer. Lab Invest. 2019; 99: 1275-86.
van Heerde WL., de Groot PG, Reutelingsperger CP. The complexity of the phospholipid binding protein annexin V. Thromb Haemost. 1995; 73: 172-79.
Wang NN, Li ZH, Zhao H, Tao YF, Xu LX, LuJ, Pan J. Molecular targeting of the oncoprotein PLK1 in pediatric acute myeloid leukemia: RO3280, a novel PLK1 inhibitor, induces apoptosis in leukemia cells. IntJ Mol Sci. 2015; 16: 1266-92.
Wang X. The expanding role of mitochondria in apoptosis. Genes Dev. 2001; 15: 2922-33.
Weichert W, Ullrich A, Schmidt M, Gekeler V, Noske A, Niesporek S, Denkert C. Expression patterns of polo-like kinase 1 in human gastric cancer. Cancer Sci. 2006; 97: 271-76.
Wong RSY. Apoptosis in cancer: From pathogenesis to treatment. J Exp Clin Cancer Res. 2011; 30: 1-14.
Wyllie AH. Apoptosis. Br J Cancer. 1993; 67: 205-08.
Wyllie AH, Kerr JF, Currie AR. Cell death: The significance of apoptosis. Int Rev Cytol. 1980; 68: 251-306.
Yulak F, Filiz AK, Joha Z, Ergul M. Mechanism of anticancer effect of ETP-45658, a PI3K/AKT/mTOR pathway inhibitor on HT-29 cells. Med Oncol. 2023; 40: 1-14.
Zamzami N, Kroemer G. The mitochondrion in apoptosis: How Pandora’s box opens. Nat Rev Mol Cell Biol. 2001; 2: 67-71.
Zamzami N, Susin SA, Marchetti P, Hirsch T, Gomez-Monterrey I, Castedo M, Kroemer G. Mitochondrial control of nuclear apoptosis. J Exp Med. 1996; 183: 1533-44.
Zeidan AM, Ridinger M, Lin TL, Becker PS, Schiller GJ, Patel PA, Wang ES. A phase ib study of onvansertib, a novel oral PLK1 inhibitor, in combination therapy for patients with relapsed or refractory acute myeloid leukemia. Clin Cancer Res. 2020; 26: 6132-40.
ZhangZ, 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: 758-67.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 Fatih Yulak, Zekeriya Keskin
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
