Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Atorvastatin Enhances Inhibitory Effects of Irradiation on Tumor Growth by Reducing MSH2 Expression Both in Prostate Cancer Cells and Xenograft Tumor Models

Author(s): Zhenhua He*, Dingkai Xu, Fuhui Shen, Fangang Zeng, Ping Qi, Zhenxing Zhai and Zhiping Wang*

Volume 22, Issue 7, 2022

Published on: 02 June, 2021

Page: [1328 - 1339] Pages: 12

DOI: 10.2174/1871520621666210602133005

Price: $65

Abstract

Background: Prostate cancer (PCa) is the fourth most common tumor in males.

Objective: This study aimed to investigate effects of atorvastatin (AS) on PCa cells proliferation and clarify the associated mechanisms.

Methods: PCa cell lines were cultured and treated with irradiation (IR) (4 Gy), AS (6 μg/ml), transfected with Bcl-2 siRNA, and then divided into different groups. Xenograft tumor mouse model was established. Bcl-2 and MSH2 gene transcription and protein expression were evaluated using RT-PCR assay and western blot assay. Plate clone formation assay was employed to examine colony formation. MTT assay was used to detect cell viabilities. Flow cytometry analysis was utilized to verify apoptosis. Co-immunoprecipitation and immuno-fluorescence assay were used to identify interaction between Bcl-2 and MSH2.

Results: IR significantly reduced colony formation, enhanced Bcl-2 and reduced MSH2 gene transcription in PCa cells compared to un-treated cells (p<0.05). AS significantly strengthened radio-therapeutic effects of IR on colony formation, decreased cell apoptosis and increased Bcl-2 gene transcription/protein expression in PCa cells compared to single IR treatment cells (p<0.05). AS combining IR down-regulated MSH2 gene transcription/protein expression in PCa cells compared to single IR treatment cells (p<0.05). Bcl-2 interacted with MSH2 both in PCa cells and tumor tissues administrating with AS. AS enhanced reductive effects of IR on tumor size of Xenograft tumor mice.

Conclusion: Atorvastatin administration enhanced inhibitory effects of IR either on PCa cells or tumor size of Xenograft tumor mice. The inhibitory effects of atorvastatin were mediated by reducing MSH2 expression and triggering interaction between Bcl-2 and MSH2, both in vitro and in vivo levels.

Keywords: Prostate cancer, atorvastatin, irradiation, Xenograft tumor, MSH2, Bcl-2.

« Previous Next »
Graphical Abstract

[1]
Chen, X.; Liu, Y.; Wu, J.; Huang, H.; Du, Z.; Zhang, K.; Zhou, D.; Hung, K.; Goodin, S.; Zheng, X. Mechanistic study of inhibitory effects of Atorvastatin and docetaxel in combination on prostate cancer. Cancer Genomics Proteomics, 2016, 13(2), 151-160.
[PMID: 26912805]
[2]
Yue, Y.; Xu, Y.; Huang, L.; Pan, D.; Bai, Z.; Wang, L.; Yang, R.; Yan, J.; Song, H.; Li, X.; Yang, M. Evaluation of a novel GLP-1R ligand for PET imaging of prostate cancer. Anticancer. Agents Med. Chem., 2019, 19(4), 509-514.
[http://dx.doi.org/10.2174/1871520618666180801101730] [PMID: 30068284]
[3]
Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global cancer statistics. CA Cancer J. Clin., 2011, 61(2), 69-90.
[http://dx.doi.org/10.3322/caac.20107] [PMID: 21296855]
[4]
Choe, K.S.; Liauw, S.L. Radiotherapeutic strategies in the management of low-risk prostate cancer. ScientificWorldJournal, 2010, 10, 1854-1869.
[http://dx.doi.org/10.1100/tsw.2010.179] [PMID: 20852828]
[5]
Vanneste, B.G.; Van Limbergen, E.J.; van Lin, E.N.; van Roermund, J.G.; Lambin, P. Prostate cancer radiation therapy: What do clinicians have to know? BioMed Res. Int., 2016, 2016, 6829875.
[http://dx.doi.org/10.1155/2016/6829875] [PMID: 28116302]
[6]
Li, Z.; Li, N.; Shen, L. MAP2K6 is associated with radiation resistance and adverse prognosis for locally advanced nasopharyngeal carcinoma patients. Cancer Manag. Res., 2018, 10, 6905-6912.
[http://dx.doi.org/10.2147/CMAR.S184689] [PMID: 30588096]
[7]
Polkinghorn, W.R.; Zelefsky, M.J. Improving outcomes in high-risk prostate cancer with radiotherapy. Rep. Pract. Oncol. Radiother., 2013, 18(6), 333-337.
[http://dx.doi.org/10.1016/j.rpor.2013.10.006] [PMID: 24416574]
[8]
Hennessey, D.; Martin, L.M.; Atzberger, A.; Lynch, T.H.; Hollywood, D.; Marignol, L. Exposure to hypoxia following irradiation increases radioresistance in prostate cancer cells. Urol. Oncol., 2013, 31(7), 1106-1116.
[http://dx.doi.org/10.1016/j.urolonc.2011.10.008] [PMID: 22130126]
[9]
Shaikh, T.; Handorf, E.A.; Meyer, J.E.; Hall, M.J.; Esnaola, N.F. Mismatch repair deficiency testing in patients with colorectal cancer and nonadherence to testing guidence in young adults. JAMA Oncol., 2018, 4(2), e173580.
[http://dx.doi.org/10.1001/jamaoncol.2017.3580] [PMID: 29121143]
[10]
Friedman, H.S.; McLendon, R.E.; Kerby, T.; Dugan, M.; Bigner, S.H.; Henry, A.J.; Ashley, D.M.; Krischer, J.; Lovell, S.; Rasheed, K.; Marchev, F.; Seman, A.J.; Cokgor, I.; Rich, J.; Stewart, E.; Colvin, O.M.; Provenzale, J.M.; Bigner, D.D.; Haglund, M.M.; Friedman, A.H.; Modrich, P.L. DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J. Clin. Oncol., 1998, 16(12), 3851-3857.
[http://dx.doi.org/10.1200/JCO.1998.16.12.3851] [PMID: 9850030]
[11]
Agarwal, S.; Suri, V.; Sharma, M.C.; Sarkar, C. Therapy and progression--induced O6-methylguanine-DNA methyltransferase and mismatch repair alterations in recurrent glioblastoma multiforme. Indian J. Cancer, 2015, 52(4), 568-573.
[http://dx.doi.org/10.4103/0019-509X.178403] [PMID: 26960480]
[12]
Jeong, J.H.; Yum, K.S.; Chang, J.Y.; Kim, M.; Ahn, J.Y.; Kim, S.; Lapchak, P.A.; Han, M.K. Dose-specific effect of simvastatin on hypoxia-induced HIF-1α and BACE expression in Alzheimer’s disease cybrid cells. BMC Neurol., 2015, 15, 127.
[http://dx.doi.org/10.1186/s12883-015-0390-5] [PMID: 26228060]
[13]
Zhang, Y.; Zhang, T. Association between statin usage and prostate cancer risk: A meta-analysis. JAMA, 2006, 295, 74-80.
[http://dx.doi.org/10.1001/jama.295.1.74]
[14]
Hsieh, H.C.; Hsu, J.C.; Lu, C.Y. 10-year trends in statin utilization in Taiwan: A retrospective study using Taiwan’s National Health Insurance Research Database. BMJ Open, 2017, 7(5), e014150.
[http://dx.doi.org/10.1136/bmjopen-2016-014150] [PMID: 28515189]
[15]
Svensson, E.; Nielsen, R.B.; Hasvold, P.; Aarskog, P.; Thomsen, R.W. Statin prescription patterns, adherence, and attainment of cholesterol treatment goals in routine clinical care: A Danish population-based study. Clin. Epidemiol., 2015, 7, 213-223.
[http://dx.doi.org/10.2147/CLEP.S78145] [PMID: 25759601]
[16]
He, Z.; Mangala, L.S.; Theriot, C.A.; Rohde, L.H.; Wu, H.; Zhang, Y. Cell killing and radiosensitizing effects of atorvastatin in PC3 prostate cancer cells. J. Radiat. Res. (Tokyo), 2012, 53(2), 225-233.
[http://dx.doi.org/10.1269/jrr.11114] [PMID: 22510595]
[17]
Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Method. Methods, 2001, 25(4), 402-408.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
[18]
Sun, Y.; Jia, X.; Gao, Q.; Liu, X.; Hou, L. The ubiquitin ligase UBE4A inhibits prostate cancer progression by targeting interleukin-like EMT inducer (ILEI). IUBMB Life, 2017, 69(1), 16-21.
[http://dx.doi.org/10.1002/iub.1585] [PMID: 27862841]
[19]
Zhou, L.; Kong, Q.; Zhang, Y.; Yang, W.; Yan, S.; Li, M.; Wang, Y.; Zhou, Y.; Yu, H.; Han, L. Glucose deprivation promotes apoptotic response to S1 by enhancing autophagy in human cervical cancer cells. Cancer Manag. Res., 2018, 10, 6195-6204.
[http://dx.doi.org/10.2147/CMAR.S184180] [PMID: 30538566]
[20]
de Rosa, N.; Rodriguez-Bigas, M.A.; Chang, G.J.; Veerapong, J.; Borras, E.; Krishnan, S.; Bednarski, B.; Messick, C.A.; Skibber, J.M.; Feig, B.W.; Lynch, P.M.; Vilar, E.; You, Y.N. DNA mismatch repair deficiency in rectal cancer: Benchmarking its impact on prognosis, neoadjuvant response prediction, and clinical cancer genetics. J. Clin. Oncol., 2016, 34(25), 3039-3046.
[http://dx.doi.org/10.1200/JCO.2016.66.6826] [PMID: 27432916]
[21]
Yu, H.; Sun, S.Q.; Gu, X.B.; Wang, W.; Gao, X.S. Atorvastatin prolongs the lifespan of radiation induced reactive oxygen species in PC-3 prostate cancer cells to enhance the cell killing effect. Oncol. Rep., 2017, 37(4), 2049-2056.
[http://dx.doi.org/10.3892/or.2017.5447] [PMID: 28260074]
[22]
Chen, B.; Zhang, M.; Xing, D.; Feng, Y. Atorvastatin enhances radiosensitivity in hypoxia-induced prostate cancer cells related with HIF-1 inhibition. Biosci. Rep., 2017, 37, BSR20170304.
[http://dx.doi.org/10.1042/BSR20170340]
[23]
Hannan, R.; Tumati, V.; Xie, X.J.; Cho, L.C.; Kavanagh, B.D.; Brindle, J.; Raben, D.; Nanda, A.; Cooley, S.; Kim, D.W.N.; Pistenmaa, D.; Lotan, Y.; Timmerman, R. Stereotactic body radiation therapy for low and intermediate risk prostate cancer-Results from a multi-institutional clinical trial. Eur. J. Cancer, 2016, 59, 142-151.
[http://dx.doi.org/10.1016/j.ejca.2016.02.014] [PMID: 27035363]
[24]
Huang, Y.L.; Lin, Y.C.; Lin, C.C.; Chen, W.M.; Chen, B.P.C.; Lee, H. High glucose induces VEGF-C expression via the LPA1/3-Akt-ROS-LEDGF signaling Aixs in human prostate cancer PC-3 cells. Cell. Physiol. Biochem., 2018, 50(2), 597-611.
[http://dx.doi.org/10.1159/000494177] [PMID: 30317243]
[25]
Tabernero, J. The role of VEGF and EGFR inhibition: Implications for combining anti-VEGF and anti-EGFR agents. Mol. Cancer Res., 2007, 5(3), 203-220.
[http://dx.doi.org/10.1158/1541-7786.MCR-06-0404] [PMID: 17374728]
[26]
Denmeade, S.R.; Isaacs, J.T. A history of prostate cancer treatment. Nat. Rev. Cancer, 2002, 2(5), 389-396.
[http://dx.doi.org/10.1038/nrc801] [PMID: 12044015]
[27]
Feldman, B.J.; Feldman, D. The development of androgen-independent prostate cancer. Nat. Rev. Cancer, 2001, 1(1), 34-45.
[http://dx.doi.org/10.1038/35094009] [PMID: 11900250]
[28]
Jones, H.M.; Fang, Z.; Sun, W.; Clark, L.H.; Stine, J.E.; Tran, A.Q.; Sullivan, S.A.; Gilliam, T.P.; Zhou, C.; Bae-Jump, V.L. Atorvastatin exhibits anti-tumorigenic and anti-metastatic effects in ovarian cancer in vitro. Am. J. Cancer Res., 2017, 7(12), 2478-2490.
[PMID: 29312801]
[29]
Zadra, G.; Photopoulos, C.; Loda, M. The fat side of prostate cancer. Biochim. Biophys. Acta, 2013, 1831(10), 1518-1532.
[http://dx.doi.org/10.1016/j.bbalip.2013.03.010] [PMID: 23562839]
[30]
Arafat, W.; Zhou, T.; Naoum, G.E.; Buchsbaum, D.J. Targeted radiotherapy potentiates the cytotoxicity of a novel anti-human DR5 monoclonal antibody and the adenovirus encoding soluble TRAIL in prostate cancer. J. Egypt. Natl. Canc. Inst., 2015, 27(4), 205-215.
[http://dx.doi.org/10.1016/j.jnci.2015.08.003] [PMID: 26385392]
[31]
Ma, Z.; Luo, Y.; Qiu, M. miR-143 induces the apoptosis of prostate cancer Lncap cells by suppressing Bcl-2 expression. Med. Sci. Monit., 2017, 23, 359-365.
[http://dx.doi.org/10.12659/MSM.899719] [PMID: 28109198]
[32]
Calastretti, A.; Gatti, G.; Quaresmini, C.; Bevilacqua, A. Down-modulation of Bcl-2 sensitizes PTEN-mutated prostate cancer cells to starvation and taxanes. Prostate, 2014, 74(14), 1411-1422.
[http://dx.doi.org/10.1002/pros.22857] [PMID: 25111376]
[33]
Rodríguez-Hernández, I.; Garcia, J.L.; Santos-Briz, A.; Hernández-Laín, A.; González-Valero, J.M.; Gómez-Moreta, J.A.; Toldos-González, O.; Cruz, J.J.; Martin-Vallejo, J.; González-Sarmiento, R. Integrated analysis of mismatch repair system in malignant astrocytomas. PLoS One, 2013, 8(9), e76401.
[http://dx.doi.org/10.1371/journal.pone.0076401] [PMID: 24073290]
[34]
Huh, J.W.; Kim, H.C.; Kim, S.H.; Park, Y.A.; Cho, Y.B.; Yun, S.H.; Lee, W.Y.; Park, H.C.; Choi, D.H.; Park, J.O.; Park, Y.S.; Chun, H.K. Mismatch repair gene expression as a predictor of tumor responses in patients with rectal cancer treated with preoperative chemoradiation. Medicine (Baltimore), 2016, 95(3), e2582.
[http://dx.doi.org/10.1097/MD.0000000000002582] [PMID: 26817916]
[35]
Guedes, L.B.; Antonarakis, E.S.; Schweizer, M.T.; Mirkheshti, N.; Almutairi, F.; Park, J.C.; Glavaris, S.; Hicks, J.; Eisenberger, M.A.; De Marzo, A.M.; Epstein, J.I.; Isaacs, W.B.; Eshleman, J.R.; Pritchard, C.C.; Lotan, T.L. MSH2 loss in primary prostate cancer. Clin. Cancer Res., 2017, 23(22), 6863-6874.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-0955] [PMID: 28790115]
[36]
Srivastava, T.; Chattopadhyay, P.; Mahapatra, A.K.; Sarkar, C.; Sinha, S. Increased hMSH2 protein expression in glioblastoma multiforme. J. Neurooncol., 2004, 66(1-2), 51-57.
[http://dx.doi.org/10.1023/B:NEON.0000013482.99032.b0] [PMID: 15015769]

Rights & Permissions Print Cite
Article Metrics
20
1
© 2024 Bentham Science Publishers | Privacy Policy