Antitumour activity of TH1579, a novel MTH1 inhibitor, against castration‑resistant prostate cancer

Hu,Mingqiu; Ning,Jing; Mao,Likai; Yu,Yuanyuan; Wu,Yu

doi:10.3892/ol.2020.12324

Antitumour activity of TH1579, a novel MTH1 inhibitor, against castration‑resistant prostate cancer

Authors:
- Mingqiu Hu
- Jing Ning
- Likai Mao
- Yuanyuan Yu
- Yu Wu
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Affiliations: Department of Urology, The Second Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233040, P.R. China
Published online on: November 19, 2020 https://doi.org/10.3892/ol.2020.12324
Article Number: 62
Copyright: © Hu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Castration‑resistant prostate cancer (CRPC) treatment still remains difficult. The aim of the present study was to determine the antitumour efficacy of the MutT homolog 1 (MTH1) inhibitor, TH1579, against castration‑resistant prostate cancer. PC‑3 and DU‑145 prostate cancer cells were treated with different concentrations of TH1579. C4‑2 cells with or without androgen receptor (AR) were also treated with TH1579 to assess AR function. Cell survival, 8‑oxo‑dG levels and DNA damage were measured using cell viability assays, western blotting, immunofluorescence analysis and flow cytometry. TH1579 inhibited CRPC cell proliferation in a dose‑dependent manner. The viabilities of PC‑3 and DU‑145 cells treated with 1 µM of TH1579 were 28.6 and 24.1%, respectively. The viabilities of C4‑2 cells with and without AR treated with 1 µM TH1579 were 10.6 and 19.0%, respectively. Moreover, TH1579 treatment increased 8‑oxo‑dG levels, as well as the number of 53BP1 and γH2A.X foci, resulting in increased DNA double‑strand breakage and apoptosis in PC‑3 and DU‑145 cells. The findings of the present study demonstrated that TH1579 exerted strong antitumour effects on CRPC cells, and may therefore be used as a potential therapeutic agent for the clinical treatment of CRPC.

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1	Wong MC, Goggins WB, Wang HH, Fung FD, Leung C, Wong SY, Ng CF and Sung JJ: Global incidence and mortality for prostate cancer: Analysis of temporal patterns and trends in 36 countries. Eur Urol. 7:862–874. 2016. View Article : Google Scholar
2	Crawford ED, Higano CS, Shore ND, Hussain M and Petrylak DP: Treating patients with metastatic castration resistant prostate cancer: A comprehensive review of available therapies. J Urol. 194:1537–1547. 2015. View Article : Google Scholar : PubMed/NCBI
3	van Dodewaard-de Jong JM, Verheul HMW, Bloemendal HJ, de Klerk JMH, Carducci MA and van den Eertwegh AJM: New Treatment options for patients with metastatic prostate cancer: What is the optimal sequence? Clin Genitourin Cancer. 13:271–279. 2015. View Article : Google Scholar : PubMed/NCBI
4	Jackson SP and Bartek J: The DNA-damage response in human biology and disease. Nature. 461:1071–1078. 2009. View Article : Google Scholar : PubMed/NCBI
5	Hah SS, Mundt JM, Kim HM, Sumbad RA, Turteltaub KW and Henderson PT: Measurement of 7,8-dihydro-8-oxo-2′-deoxyguanosine metabolism in MCF-7 cells at low concentrations using accelerator mass spectrometry. Proc Natl Acad Sci USA. 104:11203–11208. 2007. View Article : Google Scholar : PubMed/NCBI
6	Zhang Y, Du Y, Le W, Wang K, Kieffer N and Zhang J: Redox control of the survival of healthy and diseased cells. Antioxid Redox Signal. 15:2867–2908. 2011. View Article : Google Scholar : PubMed/NCBI
7	Nakabeppu Y: Cellular levels of 8-oxoguanine in either DNA or the nucleotide pool play pivotal roles in carcinogenesis and survival of cancer cells. Int J Mol Sci. 15:12543–12557. 2014. View Article : Google Scholar : PubMed/NCBI
8	Gad H, Koolmeister T, Jemth AS, Eshtad S, Jacques SA, Ström CE, Svensson LM, Schultz N, Lundback T, Einarsdottir BO, et al: MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature. 508:215–221. 2014. View Article : Google Scholar : PubMed/NCBI
9	Kennedy CH, Pass HI and Mitchell JB: Overexpression of human mutT homologue (hMTH1) protein as a marker of persistent oxidative stress in primary non-small cell lung tumors. Free Radic Biol Med. 34:1447–1457. 2003. View Article : Google Scholar : PubMed/NCBI
10	Iida T, Furuta A, Kawashima M, Nishida J, Nakabeppu Y and Iwaki T: Accumulation of 8-oxo-2′-deoxyguanosine and increased expression of hMTH1 protein in brain tumors. Neuro Oncol. 3:73–81. 2001. View Article : Google Scholar : PubMed/NCBI
11	Tu Y, Wang Z, Wang X, Yang H, Zhang P, Johnson M, Liu N, Liu H, Jin W, Zhang Y, et al: Birth of MTH1 as a therapeutic target for glioblastoma: MTH1 is indispensable for glioma tumorigenesis. Am J Transl Res. 8:2803–2811. 2016.PubMed/NCBI
12	Okamoto K, Toyokuni S, Kim WJ, Ogawa O, Kakehi Y, Arao S, Hiai H and Yoshida O: Overexpression of human mutT homologue gene messenger RNA in renal-cell carcinoma: Evidence of persistent oxidative stress in cancer. Int J Cancer. 65:437–441. 1996. View Article : Google Scholar : PubMed/NCBI
13	Zhang X, Song W, Zhou Y, Mao F, Lin Y, Guan J and Sun Q: Expression and function of MutT homolog 1 in distinct sub-types of breast cancer. Oncol Lett. 13:2161–2168. 2017. View Article : Google Scholar : PubMed/NCBI
14	Koketsu S, Watanabe T and Nagawa H: Expression of DNA repair protein: MYH, NTH1, and MTH1 in colorectal cancer. Hepatogastroenterology. 51:638–642. 2004.PubMed/NCBI
15	Akiyama S, Saeki H, Nakashima Y, Iimori M, Kitao H, Oki E. Oda Y, Nakabeppu Y, Kakeji Y and Maehara Y: Prognostic impact of MutT homolog-1 expression on esophageal squamous cell carcinoma. Cancer Med. 6:258–266. 2017. View Article : Google Scholar : PubMed/NCBI
16	Rai P, Young JJ, Burton DG, Giribaldi MG, Onder TT and Weinberg RA: Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence. Oncogene. 30:1489–1496. 2011. View Article : Google Scholar : PubMed/NCBI
17	Huber KV, Salah E, Radic B, Gridling M, Elkins JM, Stukalov A, Jemth AS, Gokturk C, Sanjiv K, Strömberg K, et al: Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. Nature. 508:222–227. 2014. View Article : Google Scholar : PubMed/NCBI
18	Warpman Berglund U, Sanjiv K, Gad H, Kalderén C, Koolmeister T, Pham T, Gokturk C, Jafari R, Maddalo G, Seashore-Ludlow B, et al: Validation and development of MTH1 inhibitors for treatment of cancer. Ann Oncol. 27:2275–2283. 2016. View Article : Google Scholar : PubMed/NCBI
19	Kettle JG, Alwan H, Bista M, Breed J, Davies NL, Eckersley K, Fillery S, Foote KM, Goodwin L, Jones DR, et al: Potent and selective inhibitors of MTH1 probe its role in cancer cell survival. J Med Chem. 59:2346–2361. 2016. View Article : Google Scholar : PubMed/NCBI
20	Petrocchi A, Leo E, Reyna NJ, Hamilton MM, Shi X, Parker CA, Mseeh F, Bardenhagen JP, Leonard P, Cross JB, et al: Identification of potent and selective MTH1 inhibitors. Bioorg Med Chem Lett. 26:1503–1507. 2016. View Article : Google Scholar : PubMed/NCBI
21	Kawamura T, Kawatani M, Muroi M, Kondoh Y, Futamura Y, Aono H, Tanaka M, Honda K and Osada H: Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival. Sci Rep. 6:265212016. View Article : Google Scholar : PubMed/NCBI
22	Scobie M, Helleday T, Koolmeister T, Jacques S, Desroses M and Jacques-cordonnier M: Pyrimidine-2,4-diamine derivatives for treatment of cancer. WO2014084778.
23	Pudelko L, Rouhi P, Sanjiv K, Gad H, Kalderén C, Höglund A, Squatrito M, Schuhmacher AJ, Edwards S, Hägerstrand D, et al: Glioblastoma and glioblastoma stem cells are dependent on functional MTH1. Oncotarget. 8:84671–84684. 2017. View Article : Google Scholar : PubMed/NCBI
24	Hua X, Sanjiv K, Gad H, Pham T, Gokturk C, Rasti A, Zhao Z, He K, Feng M, Zang Y, et al: Karonudib is a promising anticancer therapy in hepatocellular carcinoma. Ther Adv Med Oncol. 11:17588359198669602019. View Article : Google Scholar : PubMed/NCBI
25	Das I, Gad H, Brautigam L, Pudelko L, Tuminen R, Helleday T, Hansson J, Brage S and Berglund U: 1180 Effects of MTH1 inhibitor TH1579 on cutaneous melanoma. J Invest Dermat. 138:S2002018. View Article : Google Scholar
26	Einarsdottir BO, Karlsson J, Söderberg EMV, Lindberg MF, Funck-Brentano E, Jespersen H, Brynjolfsson SF, Olofsson Bagge R, Carstam L, Carstam L, et al: A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma. Cell Death Dis. 9:8102018. View Article : Google Scholar : PubMed/NCBI
27	Zhou W, Ma L, Yang J, Qiao H, Li L, Guo Q, Ma J, Zhao L, Wang J, Jiang G, et al: Potent and specific MTH1 inhibitors targeting gastric cancer. Cell Death Dis. 10:4342019. View Article : Google Scholar : PubMed/NCBI
28	Lee JW, Lee S, Ho JN, Youn JI, Byun SS and Lee E: Antitumor effects of MutT homolog 1 inhibitors in human bladder cancer cells. Biosci Biotechnol Biochem. 83:2265–2271. 2019. View Article : Google Scholar : PubMed/NCBI
29	Carroll AG, Voeller HJ, Sugars L and Gelmann EP: p53 oncogene mutations in three human prostate cancer cell lines. Prostate. 23:123–134. 1993. View Article : Google Scholar : PubMed/NCBI
30	Mamidi TKK, Wu J and Hicks C: Integrating germline and somatic variation information using genomic data for the discovery of biomarkers in prostate cancer. BMC Cancer. 19:2292019. View Article : Google Scholar : PubMed/NCBI
31	Asim M, Tarish F, Zecchini HI, Sanjiv K, Gelali E, Massie CE, Baridi A, Warren AY, Zhao W, Ogris C, et al: Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat Commun. 8:3742017. View Article : Google Scholar : PubMed/NCBI
32	Popovics P, Schally AV, Szalontay L, Block NL and Rick FG: Targeted cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), AEZS-108 (AN-152), inhibits the growth of DU-145 human castration-resistant prostate cancer in vivo and in vitro through elevating p21 and ROS levels. Oncotarget. 5:4567–4578. 2014. View Article : Google Scholar : PubMed/NCBI
33	Lorente D, Mateo J, Perez-Lopez R, de Bono JS and Attard G: Sequencing of agents in castration-resistant prostate cancer. Lancet Oncol. 16:e279–292. 2015. View Article : Google Scholar : PubMed/NCBI
34	Knudsen KE: The AR-DNA repair axis: Insights into prostate cancer aggressiveness. Can J Urol. 26 (5 Suppl 2):S22–S23. 2019.
35	Nakabeppu Y, Ohta E and Abolhassani N: MTH1 as a nucleotide pool sanitizing enzyme: Friend or foe? Free Radic Biol Med. 107:151–158. 2017. View Article : Google Scholar : PubMed/NCBI