Restricted accessResearch articleFirst published online 2024-01
Cisplatin and Procaterol Combination in Gastric Cancer? Targeting Checkpoint Kinase 1 for Cancer Drug Discovery and Repurposing by an Integrated Computational and Experimental Approach
Checkpoint kinase 1 (CHK1), a serine/threonine kinase, plays a crucial role in cell cycle arrest and is a promising therapeutic target for drug development against cancers. CHK1 coordinates cell cycle checkpoints in response to DNA damage, facilitating repair of single-strand breaks, and maintains the genome integrity in response to replication stress. In this study, we employed an integrated computational and experimental approach to drug discovery and repurposing, aiming to identify a potent CHK1 inhibitor among existing drugs. An e-pharmacophore model was developed based on the three-dimensional crystal structure of the CHK1 protein in complex with CCT245737. This model, characterized by seven key molecular features, guided the screening of a library of drugs through molecular docking. The top 10% of scored ligands were further examined, with procaterol emerging as the leading candidate. Procaterol demonstrated interaction patterns with the CHK1 active site similar to CHK1 inhibitor (CCT245737), as shown by molecular dynamics analysis. Subsequent in vitro assays, including cell proliferation, colony formation, and cell cycle analysis, were conducted on gastric adenocarcinoma cells treated with procaterol, both as a monotherapy and in combination with cisplatin. Procaterol, in synergy with cisplatin, significantly inhibited cell growth, suggesting a potentiated therapeutic effect. Thus, we propose the combined application of cisplatin and procaterol as a novel potential therapeutic strategy against human gastric cancer. The findings also highlight the relevance of CHK1 kinase as a drug target for enhancing the sensitivity of cytotoxic agents in cancer.
Get full access to this article
View all access options for this article.
References
1.
AlizadehnohiM, NabiuniM, NazariZ, et al.The synergistic cytotoxic effect of cisplatin and honey bee venom on human ovarian cancer cell line A2780cp. J Venom Res, 2012; 3:22–27.
2.
AntoniL, SodhaN, CollinsI, et al.CHK2 kinase: Cancer susceptibility and cancer therapy—Two sides of the same coin?. Nat Rev Cancer, 2007; 7(12):925–936; https://doi.org/10.1038/nrc2251
3.
ArunKG, SharanyaCS, AbhithajJ, et al.Drug repurposing against SARS-CoV-2 using E-pharmacophore based virtual screening, molecular docking and molecular dynamics with main protease as the target. J Biomol Struct Dyn, 2021; 39(13):4647–4658; https://doi.org/10.1080/07391102.2020.1779819
BandoT, FujimuraM, KasaharaK, et al.Selective beta2-adrenoceptor agonist enhances sensitivity to cisplatin in non-small cell lung cancer cell line. Oncol Rep, 2000; 7(1):49–52; https://doi.org/10.3892/or.7.1.49
6.
Chang-Yew LeowC, GerondakisS, SpencerA. MEK inhibitors as a chemotherapeutic intervention in multiple myeloma. Blood Cancer J, 2013; 3(3):105; https://doi.org/10.1038/bcj.2013.1
7.
ChenXM, LuT, LuS, et al.Structure-based and shape-complemented pharmacophore modeling for the discovery of novel checkpoint kinase 1 inhibitors. J Mol Model, 2010; 16(7):1195–1204; https://doi.org/10.1007/s00894-009-0630-y
8.
de OliveiraNK, AlmeidaMR, PontesFM, et al.Molecular docking, physicochemical properties, pharmacokinetics and toxicity of flavonoids present in euterpe oleracea martius. Curr Comput Aided Drug Des, 2021; 17(4):589–617; https://doi.org/10.2174/1573409916666200619122803
9.
DzoboK. What to Do for Increasing Cancer Burden on the African Continent? Accelerating public health diagnostics innovation for prevention and early intervention on cancers. OMICS, 2021; 25(9):567–579; https://doi: 10.1089/omi.2021.0098
10.
DuggerSA, PlattA, GoldsteinDB. Drug development in the era of precision medicine. Nat Rev Drug Discov, 2018; 17(3):183–196; https://doi.org/10.1038/nrd.2017.226
11.
FabbroD, Garcia-EcheverriaC. Targeting protein kinases in cancer therapy. Curr Opin Drug Discov Devel, 2002; 5(5):701–712.
12.
FloreaAM, BusselbergD. Cisplatin as an anti-tumor drug: Cellular mechanisms of activity, drug resistance and induced side effects. Cancers (Basel), 2011; 3(1):1351–1371; https://doi.org/10.3390/cancers3011351
13.
GalluzziL, SenovillaL, VitaleI, et al.Molecular mechanisms of cisplatin resistance. Oncogene, 2012; 31(15):1869–1883; https://doi.org/10.1038/onc.2011.384
14.
HerudkovaJ, ParuchK, KhirsariyaP, et al.Chk1 inhibitor SCH900776 effectively potentiates the cytotoxic effects of platinum-based chemotherapeutic drugs in human colon cancer cells. Neoplasia, 2017; 19(10):830–841; https://doi.org/10.1016/j.neo.2017.08.002
15.
HongJ, HuK, YuanY, et al.CHK1 targets spleen tyrosine kinase (L) for proteolysis in hepatocellular carcinoma. J Clin Invest, 2012; 122(6):2165–2175; https://doi.org/10.1172/JCI61380
16.
HsuWH, ZhaoX, ZhuJ, et al.Checkpoint kinase 1 inhibition enhances cisplatin cytotoxicity and overcomes cisplatin resistance in SCLC by promoting mitotic cell death. J Thorac Oncol, 2019; 14(6):1032–1045; https://doi.org/10.1016/j.jtho.2019.01.028
17.
JafriSH, GlassJ, ShiR, et al.Thymoquinone and cisplatin as a therapeutic combination in lung cancer: In vitro and in vivo. J Exp Clin Cancer Res, 2010; 29(1):87; https://doi.org/10.1186/1756-9966-29-87
18.
KakarSS, JalaVR, FongMY. Synergistic cytotoxic action of cisplatin and withaferin A on ovarian cancer cell lines. Biochem Biophys Res Commun, 2012; 423(4):819–825; https://doi.org/10.1016/j.bbrc.2012.06.047
19.
KarthikkeyanG, PervajeR, PervajeSK, et al.Prevention of MEK-ERK-1/2 hyper-activation underlines the neuroprotective effect of Glycyrrhiza glabra L. (Yashtimadhu) against rotenone-induced cellular and molecular aberrations. J Ethnopharmacol, 2021; 274:114025; https://doi.org/10.1016/j.jep.2021.114025
20.
KimKS, ChoiKJ, BaeS. A novel Chk1-binding peptide that enhances genotoxic sensitivity through the cellular redistribution of nuclear Chk1. Int J Mol Med, 2016; 38(5):1490–1498; https://doi.org/10.3892/ijmm.2016.2762
21.
LiangCC, ParkAY, GuanJL. In vitro scratch assay: A convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc, 2007; 2(2):329–333; https://doi.org/10.1038/nprot.2007.30
22.
LiuH, ShinSH, ChenH, et al.CDK12 and PAK2 as novel therapeutic targets for human gastric cancer. Theranostics, 2020; 10(14):6201–6215; https://doi.org/10.7150/thno.46137
23.
LuoX, ZhaoY, TangP, et al.Discovery of new small-molecule cyclin-dependent kinase 6 inhibitors through computational approaches. Mol Divers, 2021; 25(1):367–382; https://doi.org/10.1007/s11030-020-10120-3
24.
LuoY, ZhaL, LuoL, et al.[6]-Gingerol enhances the cisplatin sensitivity of gastric cancer cells through inhibition of proliferation and invasion via PI3K/AKT signaling pathway. Phytother Res, 2019; 33(5):1353–1362; https://doi.org/10.1002/ptr.6325
25.
LuongKV, WangL, RobertsBJ, et al.Cell fate determination in cisplatin resistance and chemosensitization. Oncotarget, 2016; 7(17):23383–23394; 10.18632/oncotarget.8110
26.
MalumbresM, BarbacidM. Cell cycle, CDKs and cancer: A changing paradigm. Nat Rev Cancer, 2009; 9(3):153–166; https://doi.org/10.1038/nrc2602
27.
MatthewsTP, JonesAM, CollinsI. Structure-based design, discovery and development of checkpoint kinase inhibitors as potential anticancer therapies. Expert Opin Drug Discov, 2013; 8(6):621–640; https://doi.org/10.1517/17460441.2013.788496
28.
MengF, SunG, ZhongM, et al.Anticancer efficacy of cisplatin and trichostatin A or 5-aza-2′-deoxycytidine on ovarian cancer. Br J Cancer, 2013; 108(3):579–586; https://doi.org/10.1038/bjc.2013.10
RahimifardM, BaeeriM, MousaviT, et al.Combination therapy of cisplatin and resveratrol to induce cellular aging in gastric cancer cells: Focusing on oxidative stress, and cell cycle arrest. Front Pharmacol, 2022; 13:1068863; https://doi.org/10.3389/fphar.2022.1068863
34.
RanjanA, ChauhanA, JindalT. In-silico and in-vitro evaluation of human acetylcholinesterase inhibition by organophosphates. Environ Toxicol Pharmacol, 2018; 57:131–140; https://doi.org/10.1016/j.etap.2017.12.014
35.
ReaderJC, MatthewsTP, KlairS, et al.Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing. J Med Chem, 2011; 54(24):8328–8342; https://doi.org/10.1021/jm2007326
36.
SenT, TongP, StewartCA, et al.CHK1 inhibition in small-cell lung cancer produces single-agent activity in biomarker-defined disease subsets and combination activity with cisplatin or olaparib. Cancer Res, 2017; 77(14):3870–3884; https://doi.org/10.1158/0008-5472.CAN-16-3409
SorensenCS, SyljuåsenRG, FalckJ, et al.Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. Cancer Cell, 2003; 3(3):247–258; https://doi.org/10.1016/S1535-6108(03)00048-5
39.
TaoK, YinY, ShenQ, et al.Akt inhibitor MK-2206 enhances the effect of cisplatin in gastric cancer cells. Biomed Rep, 2016; 4(3):365–368; https://doi.org/10.3892/br.2016.594
VerlindenL, Vanden BemptI, EelenG, et al.The E2F-regulated gene Chk1 is highly expressed in triple-negative estrogen receptor/progesterone receptor/HER-2 breast carcinomas. Cancer Res, 2007; 67(14):6574–6581; doi: 10.1158/0008-5472.CAN-06-3545
43.
WaltonMI, EvePD, HayesA, et al.The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eμ-MYC driven B-cell lymphoma. Oncotarget, 2016; 7(3):2329–2342; doi: 10.18632/oncotarget.4919
ZanniniL, DeliaD, BuscemiG. CHK2 kinase in the DNA damage response and beyond. J Mol Cell Biol, 2014; 6(6):442–457; https://doi.org/10.1093/jmcb/mju045
46.
ZhangY, HunterT. Roles of Chk1 in cell biology and cancer therapy. Int J Cancer, 2014; 134(5):1013–1023; https://doi.org/10.1002/ijc.28226
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
