MTH1抑制剂在癌症治疗中的研究进展
The Research Progress of MTH1 Inhibitors in Cancer Treatment
DOI: 10.12677/PI.2018.72004, PDF,    科研立项经费支持
作者: 狄蓉蓉, 康楠楠, 刘 煜*：中国药科大学生命科学与技术学院，江苏 南京；王 蕾, 赖宜生：中国药科大学新药研究中心，江苏 南京
关键词: MTH1；癌症治疗；ROS；DNA氧化损伤；MTH1抑制剂；MTH1； Cancer Treatment； ROS； DNA Oxidative Damage； MTH1 Inhibitors
摘要: MTH1 (MutT homolog 1)作为一种焦磷酸酶，能够高效清理核苷酸池中的氧化核苷酸，从而保护快速增殖的癌细胞免受高水平ROS带来的致命损伤，但是正常细胞在缺乏MTH1酶时依旧能够通过其他替补途径修复DNA氧化损伤得以存活。在正常细胞及癌细胞中MTH1必要性的显著差异使得靶向MTH1治疗癌症这一疗法成为可能，临床前研究表明，MTH1活性被抑制后或者当MTH1缺乏时能够抑制多种癌症细胞的增殖，且未观察到明显的毒副作用，完美地弥补了传统癌症疗法的种种不足，为癌症疾病的彻底根治带来希望。本文将围绕癌症治疗的瓶颈、ROS与癌症及MTH1的关系、MTH1与癌症相关的功能作用、MTH1抑制剂的发展几点进行综述，旨在阐明癌症治疗手段的新发展，为新药开发奠定理论基础。
Abstract: MTH1 (MutT homolog 1) can effectively sanitize oxidized nucleotides in the nucleotides pool to pro-tect cancer cells from fatal damage caused by high levels of ROS (reactive oxygen species). In con-trast, the normal cells can repair DNA oxidative damage to survive by the alternative pathway when MTH1 is inhibited. The different importance of MTH1 between normal and cancer cells makes it possible to target MTH1 in treating cancer. Preclinical studies have shown that the inhibition of MTH1 activity or the lack of MTH1 has obvious anti-tumor effect but without side effects, which can perfectly make up for the shortcomings of traditional cancer treatments. To illustrate the new de-velopment of cancer treatments and lay the foundation for new drug development, we will summa-rize the major obstacle to the successful treatment of cancer and the relationship between ROS and cancer and MTH1, illuminate the functional role for MTH1 in tumor biology, and explore the devel-opment of MTH1 inhibitors.
文章引用：狄蓉蓉, 康楠楠, 王蕾, 赖宜生, 刘煜. MTH1抑制剂在癌症治疗中的研究进展[J]. 药物资讯, 2018, 7(2): 15-20. https://doi.org/10.12677/PI.2018.72004

参考文献

[1] Torre, L.A., Bray, F., Siegel, R.L., et al. (2015) Global Cancer Statistics, 2012. Ca A Cancer Journal for Clinicians, 65, 87-108. [Google Scholar] [CrossRef] [PubMed]
[2] Wang, J.Y., Liu, G.Z., Wilmott, J.S., et al. (2017) Skp2-Mediated Stabilization of MTH1 Promotes Survival of Melanoma Cells upon Oxidative Stress. Cancer Research, 77, 6226. [Google Scholar] [CrossRef] 
[3] Gad, H., Koolmeister, T., Jemth, A.S., et al. (2014) MTH1 Inhibition Eradicates Cancer by Preventing Sanitation of the dNTP Pool. Nature, 508, 215. [Google Scholar] [CrossRef] [PubMed]
[4] Torre, L.A., Siegel, R.L., Ward, E.M., et al. (2016) Global Cancer Inci-dence and Mortality Rates and Trends—An Update. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology, 25, 16. [Google Scholar] [CrossRef] 
[5] (2013) Breakthrough of the Year 2013. Notable Develop-ments. Science, 342, 1435.
[6] Banasavadi-Siddegowda, Y.K., Russell, L., Frair, E., Karkhanis, V.A., et al. (2016) PRMT5-PTEN Molecular Pathway Regulates Senescence and Self-Renewal of Primary Glioblastoma Neurosphere Cells. Oncogene, 36.
[7] Li, X., Li, L., Huang, Y., et al. (2017) Synergistic Therapy of Chemotherapeutic Drugs and MTH1 Inhibitors Using a pH-Sensitive Polymeric Delivery System for Oral Squamous Cell Carcinoma. Biomaterials Science, 5, 2068. [Google Scholar] [CrossRef] 
[8] Helleday, T. (2015) Poisoning Cancer Cells with Oxidized Nucleosides. New England Journal of Medicine, 373, 1570-1571. [Google Scholar] [CrossRef] 
[9] Wang, J.Y., Jin, L., Yan, X.G., et al. (2016) Reactive Oxygen Species Dictate the Apoptotic Response of Melanoma Cells to TH588. Journal of Investigative Dermatology, 136, 2277-2286. [Google Scholar] [CrossRef] [PubMed]
[10] Sharma, P. and Allison, J.P. (2015) The Future of Immune Checkpoint Therapy. Science, 348, 56. [Google Scholar] [CrossRef] [PubMed]
[11] Helleday, T. (2014) Cancer Phenotypic Lethality, Exemplified by the Non-Essential MTH1 Enzyme Being Required for Cancer Survival. Annals of Oncology Official Journal of the European Society for Medical Oncology, 25, 1253-1255. [Google Scholar] [CrossRef] [PubMed]
[12] Smits, V.A. and Gil-lespie, D.A. (2014) Cancer Therapy. Cell Cycle, 13, 2330-2333. [Google Scholar] [CrossRef] [PubMed]
[13] APANakabeppu, Y. (2014) Cellular Levels of 8-Oxoguanine in either DNA or the Nucleotide Pool Play Pivotal Roles in Carcinogenesis and Survival of Cancer Cells. International Journal of Mo-lecular Sciences, 15, 12543-12557. [Google Scholar] [CrossRef] [PubMed]
[14] Nakabeppu, Y., Ohta, E. and Abolhassani, N. (2016) MTH1 as a Nu-cleotide Pool Sanitizing Enzyme: Friend or Foe? Free Radical Biology & Medicine, 107, 151-158.
[15] Salman, K.A. and Ashraf, S. (2015) Reactive Oxygen Species: A Link between Chronic Inflammation and Cancer. Asia-Pacific Journal of Molecular Biology and Biotechnology, 22, 42-49.
[16] Venza, M., Visalli, M., Beninati, C., et al. (2015) Cellular Mechanisms of Oxidative Stress and Action in Melanoma. Oxidative Medicine & Cellular Longevity, 2015, Article ID: 481782. [Google Scholar] [CrossRef] [PubMed]
[17] Carter, M., Jemth, A.S., Hagenkort, A., et al. (2015) Crystal Structure, Biochemical and Cellular Activities Demonstrate Separate Functions of MTH1 and MTH2. Nature Communi-cations, 6, 7871. [Google Scholar] [CrossRef] [PubMed]
[18] Dan, D. and He, C. (2014) Cancer: Damage Prevention Targeted. Nature, 508, 191-192. [Google Scholar] [CrossRef] [PubMed]
[19] Huber, K.V., Salah, E., Radic, B., et al. (2014) Stereospecific Targeting of MTH1 by (S)-Crizotinib as an Anticancer Strategy. Nature, 508, 222-227. [Google Scholar] [CrossRef] [PubMed]
[20] Eshtad, S. (2017) Targeting DNA Repair Pathways for Cancer Therapy. PhD Thesis, Karolinska Institutet, Stockholm.
[21] Abbas, H.H.K., Alhamoudi, K.M.H., Evans, M.D., et al. (2017) MTH1 Deficiency Selectively Increases Non-Cytotoxic Oxidative DNA Damage in Lung Cancer Cells: More Bad News than Good?[CrossRef] 
[22] Sohraby, F., Bagheri, M., Javaheri, M.M., et al. (2017) In Silico Prediction of New Inhibitors for the Nucleotide Pool Sanitizing Enzyme, MTH1, using Drug Repurposing. Journal of Biomolecular Structure & Dynamics. [Google Scholar] [CrossRef] [PubMed]
[23] Samaranayake, G.J., Huynh, M. and Rai, P. (2017) MTH1 as a Chemotherapeutic Target: The Elephant in the Room. Cancers, 9, E47. [Google Scholar] [CrossRef] [PubMed]
[24] Akiyama, S., Saeki, H., Nakashima, Y., et al. (2017) Prognostic Im-pact of MutT Homolog-1 Expression on Esophageal Squamous Cell Carcinoma. Cancer Medicine, 6, 258-266. [Google Scholar] [CrossRef] [PubMed]
[25] 康从民, 王晓丽. 核酸氧化损伤修复酶MTH1及其抑制剂的研究进展[J]. 中国药理学通报, 2016, 32(8): 1044-1048.
[26] Kettle, J.G., Alwan, H., Bista, M., et al. (2016) Potent and Selec-tive Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival. Journal of Medicinal Chemistry, 59, 2346-2361. [Google Scholar] [CrossRef] [PubMed]
[27] Tatsuro, K., Makoto, K., Makoto, M., et al. (2016) Proteomic Profiling of Small-Molecule Inhibitors Reveals Dispensability of MTH1 for Cancer Cell Survival. Scientific Reports, 6, Article No. 26521. [Google Scholar] [CrossRef] [PubMed]
[28] Ellermann, M., Eheim, A., Rahm, F., et al. (2017) Novel Class of Potent and Cellularly Active Inhibitors De-Validates MTH1 as Broad-Spectrum Cancer Target. ACS Chemical Biology, 12, 1986-1992. [Google Scholar] [CrossRef] [PubMed]
[29] Warpman, B.U., Sanjiv, K., Gad, H., et al. (2016) Validation and Development of MTH1 Inhibitors for Treatment of Cancer. Annals of Oncology Official Journal of the European Society for Medical Oncology, 27, 2275-2283. [Google Scholar] [CrossRef] [PubMed]