Synthesis and pharmacological evaluation of novel epidermal growth factor receptor inhibitors against prostate tumor cells

Zhi,Yi; Wu,Xiaojun; Shen,Wenhao; Wang,Yongquan; Zhou,Xiaozhou; He,Peng; Pan,Jinhong; Chen,Zhiwen; Li,Weibing; Zhou,Zhansong

doi:10.3892/ol.2018.9438

Synthesis and pharmacological evaluation of novel epidermal growth factor receptor inhibitors against prostate tumor cells

Authors:
- Yi Zhi
- Xiaojun Wu
- Wenhao Shen
- Yongquan Wang
- Xiaozhou Zhou
- Peng He
- Jinhong Pan
- Zhiwen Chen
- Weibing Li
- Zhansong Zhou
View Affiliations

Affiliations: Urology Institute of People Liberation Army, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China, Department of Urology, Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, P.R. China
Published online on: September 14, 2018 https://doi.org/10.3892/ol.2018.9438
Pages: 6522-6530
Copyright: © Zhi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to investigate the activities of novel synthetic epidermal growth factor receptor (EGFR) inhibitors (ZINC05463076, ZINC2102846 and ZINC19901103) against prostate tumors, in vitro models and investigate the potential underlying mechanisms. A panel of prostate tumor cell lines (LNCaP, DU‑145, PC‑3 and LNCaP‑AI cells) were used to evaluate antitumor activity of ZINC05463076, ZINC2102846, and ZINC19901103 in vitro. Cell growth and clonal formation were determined by MTT assay and Soft agar colony formation assay, respectively. An EGFR kinase assay following treatment of the compounds was performed by ELISA. Cell cycle‑regulating proteins, including cyclin‑dependent kinase (CDK)1, CKD2, CKD4 and inhibitory effects of these compounds on downstream signaling were analyzed by western blotting. Flow cytometry was performed to investigate apoptosis and cell cycle phases of the treated cells. It was revealed that all compounds synthesized in the present study demonstrated significant EGFR inhibition abilities, compared with approved EGFR inhibitor drug gefitinib. Treatment of LNCaP, DU‑145, PC3 and LNCaP‑AI cells with these compounds revealed cell proliferation inhibition and colony formation suppression dose‑dependently in vitro. The agents impaired phosphorylation of EGFR and extracellular signal‑regulated kinase 1/2 and suppressed their downstream signaling. In addition, these novel synthetic agents decreased the expression level of survivin, which may induce G1 cell cycle phase arrest and cell apoptosis in PCa cells subsequently. Collectively, ZINC05463076, ZINC2102846 and ZINC19901103 exhibited significant antitumor activity in human prostate tumors in vitro, by inhibiting EGFR and promoting apoptosis, which suggested a rationale for clinical development in prostate tumor therapy.

View Figures

View References

1	Gaudreau PO, Stagg J, Soulières D and Saad F: The present and future of biomarkers in prostate cancer: Proteomics, genomics, and immunology advancements. Biomark Cancer. 8 Suppl 2:S15–S33. 2016.
2	Hong JH and Kim IY: Nonmetastatic castration-resistant prostate cancer. Korean J Urol. 55:153–160. 2014. View Article : Google Scholar : PubMed/NCBI
3	Wang Y, Kreisberg JI and Ghosh PM: Cross-talk between the androgen receptor and the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer. Curr Cancer Drug Targets. 7:591–604. 2007. View Article : Google Scholar : PubMed/NCBI
4	Feitelson MA, Arzumanyan A, Kulathinal RJ, Blain SW, Holcombe RF, Mahajna J, Marino M, Martinez-Chantar ML, Nawroth R, Sanchez-Garcia I, et al: Sustained proliferation in cancer: Mechanisms and novel therapeutic targets. Semin Cancer Biol. 35 Suppl:S25–S54. 2015. View Article : Google Scholar : PubMed/NCBI
5	Kwabi-Addo B, Ozen M and Ittmann M: The role of fibroblast growth factors and their receptors in prostate cancer. Endocr Relat Cancer. 11:709–724. 2004. View Article : Google Scholar : PubMed/NCBI
6	Corn PG, Wang F, McKeehan WL and Navone N: Targeting fibroblast growth factor pathways in prostate cancer. Clin Cancer Res. 19:5856–5866. 2013. View Article : Google Scholar : PubMed/NCBI
7	Chen H, Zhou L, Wu X, Li R, Wen J, Sha J and Wen X: The PI3K/AKT pathway in the pathogenesis of prostate cancer. Front Biosci (Landmark Ed). 21:1084–1091. 2016. View Article : Google Scholar : PubMed/NCBI
8	Proverbs-Singh T, Feldman JL, Morris MJ, Autio KA and Traina TA: Targeting the androgen receptor in prostate and breast cancer: Several new agents in development. Endocr Relat Cancer. 22:R87–R106. 2015. View Article : Google Scholar : PubMed/NCBI
9	Cozza G, Pinna LA and Moro S: Protein kinase CK2 inhibitors: A patent review. Expert Opin Ther Pat. 22:1081–1097. 2012. View Article : Google Scholar : PubMed/NCBI
10	Mahapatra DK, Asati V and Bharti SK: MEK inhibitors in oncology: A patent review (2015-Present). Expert Opin Ther Pat. 27:887–906. 2017. View Article : Google Scholar : PubMed/NCBI
11	Hospital A, Goñi JR, Orozco M and Gelpí JL: Molecular dynamics simulations: Advances and applications. Adv Appl Bioinform Chem. 8:37–47. 2015.PubMed/NCBI
12	Ferreira LG, Dos Santos RN, Oliva G and Andricopulo AD: Molecular docking and structure-based drug design strategies. Molecules. 20:13384–13421. 2015. View Article : Google Scholar : PubMed/NCBI
13	Rao CM, Yejella RP, Rehman RS and Basha SH: Molecular docking based screening of novel designed chalcone series of compounds for their anti-cancer activity targeting EGFR kinase domain. Bioinformation. 11:322–329. 2015. View Article : Google Scholar : PubMed/NCBI
14	Li S, Sun X, Zhao H, Tang Y and Lan M: Discovery of novel EGFR tyrosine kinase inhibitors by structure-based virtual screening. Bioorg Med Chem Lett. 22:4004–4009. 2012. View Article : Google Scholar : PubMed/NCBI
15	Sun XQ, Chen L, Li YZ, Li WH, Liu GX, Tu YQ and Tang Y: Structure-based ensemble-QSAR model: A novel approach to the study of the EGFR tyrosine kinase and its inhibitors. Acta Pharmacol Sin. 35:301–310. 2014. View Article : Google Scholar : PubMed/NCBI
16	Singh VK and Coumar MS: Ensemble-based virtual screening: Identification of a potential allosteric inhibitor of Bcr-Abl. J Mol Model. 23:2182017. View Article : Google Scholar : PubMed/NCBI
17	Kellenberger E, Rodrigo J, Muller P and Rognan D: Comparative evaluation of eight docking tools for docking and virtual screening accuracy. Proteins. 57:225–242. 2004. View Article : Google Scholar : PubMed/NCBI
18	Huang N, Shoichet BK and Irwin JJ: Benchmarking sets for molecular docking. J Med Chem. 49:6789–6801. 2006. View Article : Google Scholar : PubMed/NCBI
19	McNaughton M, Pitman M, Pitson SM, Pyne NJ and Pyne S: Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells. Oncotarget. 7:16663–16675. 2016. View Article : Google Scholar : PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Lokadasan R, James FV, Narayanan G and Prabhakaran PK: Targeted agents in epithelial ovarian cancer: Review on emerging therapies and future developments. Ecancermedicalscience. 10:6262016. View Article : Google Scholar : PubMed/NCBI
22	Huskey NE, Guo T, Evason KJ, Momcilovic O, Pardo D, Creasman KJ, Judson RL, Blelloch R, Oakes SA, Hebrok M and Goga A: CDK1 inhibition targets the p53-NOXA-MCL1 axis, selectively kills embryonic stem cells, and prevents teratoma formation. Stem Cell Reports. 4:374–389. 2015. View Article : Google Scholar : PubMed/NCBI
23	Chen X, Guo D, Zhu Y, Xian F, Liu S, Wu L and Lou X: Nuclear phosphoproteomics analysis reveals that CDK1/2 are involved in EGF-regulated constitutive pre-mRNA splicing in MDA-MB-468 cells. J Proteomics. 141:77–84. 2016. View Article : Google Scholar : PubMed/NCBI
24	Xiao X, Wu J, Zhu X, Zhao P, Zhou J, Liu QQ, Zheng L, Zeng M, Liu R and Huang W: Induction of cell cycle arrest and apoptosis in human nasopharyngeal carcinoma cells by ZD6474, an inhibitor of VEGFR tyrosine kinase with additional activity against EGFR tyrosine kinase. Int J Cancer. 121:2095–2104. 2007. View Article : Google Scholar : PubMed/NCBI
25	Rigas AC, Robson CN and Curtin NJ: Therapeutic potential of CDK inhibitor NU2058 in androgen-independent prostate cancer. Oncogene. 26:7611–7619. 2007. View Article : Google Scholar : PubMed/NCBI
26	Hurtado A, Pinós T, Barbosa-Desongles A, López-Avilés S, Barquinero J, Petriz J, Santamaria-Martínez A, Morote J, de Torres I, Bellmunt J, et al: Estrogen receptor beta displays cell cycle-dependent expression and regulates the G1 phase through a non-genomic mechanism in prostate carcinoma cells. Cell Oncol. 30:349–365. 2008.PubMed/NCBI
27	Wang H, Zhang C, Rorick A, Wu D, Chiu M, Thomas-Ahner J, Chen Z, Chen H, Clinton SK, Chan KK and Wang Q: CCI-779 inhibits cell-cycle G2-M progression and invasion of castration-resistant prostate cancer via attenuation of UBE2C transcription and mRNA stability. Cancer Res. 71:4866–4876. 2011. View Article : Google Scholar : PubMed/NCBI
28	Comstock CE, Augello MA, Goodwin JF, de Leeuw R, Schiewer MJ, Ostrander WF Jr, Burkhart RA, McClendon AK, McCue PA, Trabulsi EJ, et al: Targeting cell cycle and hormone receptor pathways in cancer. Oncogene. 32:5481–5491. 2013. View Article : Google Scholar : PubMed/NCBI
29	Chen J: The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb Perspect Med. 6:a0261042016. View Article : Google Scholar : PubMed/NCBI
30	Purev E, Cai D, Miller E, Swoboda R, Mayer T, Klein-Szanto A, Marincola FM, Mick R, Otvos L, Wunner W, et al: Immune responses of breast cancer patients to mutated epidermal growth factor receptor (EGF-RvIII, Delta EGF-R, and de2-7 EGF-R). J Immunol. 173:6472–6480. 2004. View Article : Google Scholar : PubMed/NCBI
31	Werry TD, Christopoulos A and Sexton PM: Mechanisms of ERK1/2 regulation by seven-transmembrane-domain receptors. Curr Pharm Des. 12:1683–1702. 2006. View Article : Google Scholar : PubMed/NCBI
32	Uribe P and Gonzalez S: Epidermal growth factor receptor (EGFR) and squamous cell carcinoma of the skin: Molecular bases for EGFR-targeted therapy. Pathol Res Pract. 207:337–342. 2011. View Article : Google Scholar : PubMed/NCBI
33	Karandish F and Mallik S: Biomarkers and targeted therapy in pancreatic cancer. Biomark Cancer. 8 Suppl 1:S27–S35. 2016.
34	Rivadeneira DB, Caino MC, Seo JH, Angelin A, Wallace DC, Languino LR and Altieri DC: Survivin promotes oxidative phosphorylation, subcellular mitochondrial repositioning, and tumor cell invasion. Sci Signal. 8:ra802015. View Article : Google Scholar : PubMed/NCBI
35	Chen X, Duan N, Zhang C and Zhang W: Survivin and tumorigenesis: Molecular mechanisms and therapeutic strategies. J Cancer. 7:314–323. 2016. View Article : Google Scholar : PubMed/NCBI
36	Lim EJ, Heo J and Kim YH: Tunicamycin promotes apoptosis in leukemia cells through ROS generation and downregulation of survivin expression. Apoptosis. 20:1087–1098. 2015. View Article : Google Scholar : PubMed/NCBI
37	Garg H, Suri P, Gupta JC, Talwar GP and Dubey S: Survivin: A unique target for tumor therapy. Cancer Cell Int. 16:492016. View Article : Google Scholar : PubMed/NCBI
38	Hakonen E, Ustinov J, Palgi J, Miettinen PJ and Otonkoski T: EGFR signaling promotes β-cell proliferation and survivin expression during pregnancy. PLoS One. 9:e936512014. View Article : Google Scholar : PubMed/NCBI