蛋白酶体抑制剂治疗脑胶质瘤的研究进展
Research Progress on Proteasome Inhibitors for the Treatment of Glioma
摘要: 脑胶质瘤是成人中枢神经系统中最常见的恶性肿瘤之一，尤其是恶性程度高的胶质母细胞瘤，其预后极差，传统的手术、放疗和化疗等治疗方式效果有限。蛋白酶体抑制剂作为一种新兴的抗肿瘤治疗方式，通过抑制细胞蛋白降解的通路，干扰细胞内蛋白质稳态，进而诱导肿瘤细胞死亡。本文综述了蛋白酶体抑制剂在脑胶质瘤治疗中的作用机制、临床前和临床研究进展，并探讨了其应用前景和面临的挑战。
Abstract: Gliomas are one of the most common malignant tumors in the adult central nervous system, especially highly malignant glioblastomas, which have a very poor prognosis. Traditional treatments such as surgery, radiotherapy, and chemotherapy have limited effectiveness. Proteasome inhibitors, as an emerging anti-tumor therapy, interfere with intracellular protein homeostasis by inhibiting the pathway of cellular protein degradation, thereby inducing tumor cell death. This article reviews the mechanism of action, preclinical and clinical research progress of proteasome inhibitors in the treatment of glioblastoma, and explores their application prospects and challenges.
文章引用：孔繁栋, 韩光魁, 沈嵩民. 蛋白酶体抑制剂治疗脑胶质瘤的研究进展[J]. 临床个性化医学, 2025, 4(1): 244-251. https://doi.org/10.12677/jcpm.2025.41038

参考文献

[1] Weller, M., Wen, P.Y., Chang, S.M., Dirven, L., Lim, M., Monje, M., et al. (2024) Glioma. Nature Reviews Disease Primers, 10, Article No. 33. [Google Scholar] [CrossRef] [PubMed]
[2] Ostrom, Q.T., Price, M., Neff, C., Cioffi, G., Waite, K.A., Kruchko, C., et al. (2023) CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2016-2020. Neuro-Oncology, 25, iv1-iv99. [Google Scholar] [CrossRef] [PubMed]
[3] Louis, D.N., Perry, A., Wesseling, P., Brat, D.J., Cree, I.A., Figarella-Branger, D., et al. (2021) The 2021 WHO Classification of Tumors of the Central Nervous System: A Summary. Neuro-Oncology, 23, 1231-1251. [Google Scholar] [CrossRef] [PubMed]
[4] Śledzińska, P., Bebyn, M., Furtak, J., Koper, A. and Koper, K. (2022) Current and Promising Treatment Strategies in Glioma. Reviews in the Neurosciences, 34, 483-516. [Google Scholar] [CrossRef] [PubMed]
[5] Mehta, N.H., Shah, H.A. and D’Amico, R.S. (2023) Sonodynamic Therapy and Sonosensitizers for Glioma Treatment: A Systematic Qualitative Review. World Neurosurgery, 178, 60-68. [Google Scholar] [CrossRef] [PubMed]
[6] Han, D., Wang, L., Jiang, S. and Yang, Q. (2023) The Ubiquitin-Proteasome System in Breast Cancer. Trends in Molecular Medicine, 29, 599-621. [Google Scholar] [CrossRef] [PubMed]
[7] Kim, Y.J., Lee, Y., Shin, H., Hwang, S., Park, J. and Song, E.J. (2023) Ubiquitin-Proteasome System as a Target for Anticancer Treatment—An Update. Archives of Pharmacal Research, 46, 573-597. [Google Scholar] [CrossRef] [PubMed]
[8] LaPlante, G. and Zhang, W. (2021) Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors. Cancers, 13, Article 3079. [Google Scholar] [CrossRef] [PubMed]
[9] Abbas, R. and Larisch, S. (2021) Killing by Degradation: Regulation of Apoptosis by the Ubiquitin-Proteasome-System. Cells, 10, Article 3465. [Google Scholar] [CrossRef] [PubMed]
[10] Park, J., Cho, J. and Song, E.J. (2020) Ubiquitin-Proteasome System (UPS) as a Target for Anticancer Treatment. Archives of Pharmacal Research, 43, 1144-1161. [Google Scholar] [CrossRef] [PubMed]
[11] Gavriatopoulou, M., Malandrakis, P., Ntanasis-Stathopoulos, I. and Dimopoulos, M.A. (2021) Nonselective Proteasome Inhibitors in Multiple Myeloma and Future Perspectives. Expert Opinion on Pharmacotherapy, 23, 335-347. [Google Scholar] [CrossRef] [PubMed]
[12] Kane, R.C., Bross, P.F., Farrell, A.T. and Pazdur, R. (2003) Velcade®: U.S. FDA Approval for the Treatment of Multiple Myeloma Progressing on Prior Therapy. The Oncologist, 8, 508-513. [Google Scholar] [CrossRef] [PubMed]
[13] Palumbo, A., Chanan-Khan, A., Weisel, K., Nooka, A.K., Masszi, T., Beksac, M., et al. (2016) Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. New England Journal of Medicine, 375, 754-766. [Google Scholar] [CrossRef] [PubMed]
[14] Durie, B.G.M., Hoering, A., Abidi, M.H., Rajkumar, S.V., Epstein, J., Kahanic, S.P., et al. (2017) Bortezomib with Lenalidomide and Dexamethasone versus Lenalidomide and Dexamethasone Alone in Patients with Newly Diagnosed Myeloma without Intent for Immediate Autologous Stem-Cell Transplant (SWOG S0777): A Randomised, Open-Label, Phase 3 Trial. The Lancet, 389, 519-527. [Google Scholar] [CrossRef] [PubMed]
[15] Ciechanover, A. and Kwon, Y.T. (2017) Protein Quality Control by Molecular Chaperones in Neurodegeneration. Frontiers in Neuroscience, 11, Article 185. [Google Scholar] [CrossRef] [PubMed]
[16] Han, D., Li, S., Xia, Q., Meng, X. and Dong, L. (2021) Overexpressed Smurf1 Is Degraded in Glioblastoma Cells through Autophagy in a P62‐Dependent Manner. FEBS Open Bio, 12, 118-129. [Google Scholar] [CrossRef] [PubMed]
[17] Swatek, K.N. and Komander, D. (2016) Ubiquitin Modifications. Cell Research, 26, 399-422. [Google Scholar] [CrossRef] [PubMed]
[18] Sheng, X., Xia, Z., Yang, H. and Hu, R. (2023) The Ubiquitin Codes in Cellular Stress Responses. Protein & Cell, 15, 157-190. [Google Scholar] [CrossRef] [PubMed]
[19] Mansour, M.A. (2018) Ubiquitination: Friend and Foe in Cancer. The International Journal of Biochemistry & Cell Biology, 101, 80-93. [Google Scholar] [CrossRef] [PubMed]
[20] Liao, Y., Sumara, I. and Pangou, E. (2022) Non-Proteolytic Ubiquitylation in Cellular Signaling and Human Disease. Communications Biology, 5, Article No. 114. [Google Scholar] [CrossRef] [PubMed]
[21] Mattiroli, F. and Penengo, L. (2021) Histone Ubiquitination: An Integrative Signaling Platform in Genome Stability. Trends in Genetics, 37, 566-581. [Google Scholar] [CrossRef] [PubMed]
[22] Spano, D. and Catara, G. (2023) Targeting the Ubiquitin-Proteasome System and Recent Advances in Cancer Therapy. Cells, 13, Article 29. [Google Scholar] [CrossRef] [PubMed]
[23] Li, Y., Li, S. and Wu, H. (2022) Ubiquitination-Proteasome System (UPS) and Autophagy Two Main Protein Degradation Machineries in Response to Cell Stress. Cells, 11, Article 851. [Google Scholar] [CrossRef] [PubMed]
[24] Cammann, C., Israel, N., Slevogt, H. and Seifert, U. (2022) Recycling and Reshaping—E3 Ligases and Dubs in the Initiation of T Cell Receptor-Mediated Signaling and Response. International Journal of Molecular Sciences, 23, Article 3424. [Google Scholar] [CrossRef] [PubMed]
[25] Newton, K. and Gitlin, A.D. (2022) Deubiquitinases in Cell Death and Inflammation. Biochemical Journal, 479, 1103-1119. [Google Scholar] [CrossRef] [PubMed]
[26] Dagar, G., Kumar, R., Yadav, K.K., Singh, M. and Pandita, T.K. (2023) Ubiquitination and deubiquitination: Implications on cancer therapy. Biochimica et Biophysica Acta (BBA)—Gene Regulatory Mechanisms, 1866, Article ID: 194979. [Google Scholar] [CrossRef] [PubMed]
[27] Ge, F., Li, Y., Yuan, T., Wu, Y., He, Q., Yang, B., et al. (2022) Deubiquitinating Enzymes: Promising Targets for Drug Resistance. Drug Discovery Today, 27, 2603-2613. [Google Scholar] [CrossRef] [PubMed]
[28] Gavriatopoulou, M., Malandrakis, P., Ntanasis-Stathopoulos, I. and Dimopoulos, M.A. (2021) Nonselective Proteasome Inhibitors in Multiple Myeloma and Future Perspectives. Expert Opinion on Pharmacotherapy, 23, 335-347. [Google Scholar] [CrossRef] [PubMed]
[29] Roeten, M.S.F., Cloos, J. and Jansen, G. (2017) Positioning of Proteasome Inhibitors in Therapy of Solid Malignancies. Cancer Chemotherapy and Pharmacology, 81, 227-243. [Google Scholar] [CrossRef] [PubMed]
[30] Gozdz, A. (2023) Proteasome Inhibitors against Glioblastoma—Overview of Molecular Mechanisms of Cytotoxicity, Progress in Clinical Trials, and Perspective for Use in Personalized Medicine. Current Oncology, 30, 9676-9688. [Google Scholar] [CrossRef] [PubMed]
[31] Manasanch, E.E. and Orlowski, R.Z. (2017) Proteasome Inhibitors in Cancer Therapy. Nature Reviews Clinical Oncology, 14, 417-433. [Google Scholar] [CrossRef] [PubMed]
[32] Leonardo-Sousa, C., Carvalho, A.N., Guedes, R.A., Fernandes, P.M.P., Aniceto, N., Salvador, J.A.R., et al. (2022) Revisiting Proteasome Inhibitors: Molecular Underpinnings of Their Development, Mechanisms of Resistance and Strategies to Overcome Anti-Cancer Drug Resistance. Molecules, 27, Article 2201. [Google Scholar] [CrossRef] [PubMed]
[33] Tang, J., Yang, L., Chen, J., Li, Q., Zhu, L., Xu, Q., et al. (2019) Bortezomib Inhibits Growth and Sensitizes Glioma to Temozolomide (TMZ) via Down-Regulating the FOXM1-Survivin Axis. Cancer Communications, 39, Article No. 81. [Google Scholar] [CrossRef] [PubMed]
[34] Johansson, P., Krona, C., Kundu, S., Doroszko, M., Baskaran, S., Schmidt, L., et al. (2020) A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma. Cell Reports, 32, Article ID: 107897. [Google Scholar] [CrossRef] [PubMed]
[35] Yin, D., Zhou, H., Kumagai, T., Liu, G., Ong, J.M., Black, K.L., et al. (2004) Proteasome Inhibitor PS-341 Causes Cell Growth Arrest and Apoptosis in Human Glioblastoma Multiforme (GBM). Oncogene, 24, 344-354. [Google Scholar] [CrossRef] [PubMed]
[36] Yoo, Y.D., Lee, D., Cha‐Molstad, H., Kim, H., Mun, S.R., Ji, C., et al. (2016) Glioma‐Derived Cancer Stem Cells Are Hypersensitive to Proteasomal Inhibition. EMBO reports, 18, 150-168. [Google Scholar] [CrossRef] [PubMed]
[37] Bota, D.A., Alexandru, D., Keir, S.T., Bigner, D., Vredenburgh, J. and Friedman, H.S. (2013) Proteasome Inhibition with Bortezomib Induces Cell Death in GBM Stem-Like Cells and Temozolomide-Resistant Glioma Cell Lines, but Stimulates GBM Stem-Like Cells’ VEGF Production and Angiogenesis. Journal of Neurosurgery, 119, 1415-1423. [Google Scholar] [CrossRef] [PubMed]
[38] Rahman, M.A., Gras Navarro, A., Brekke, J., Engelsen, A., Bindesbøll, C., Sarowar, S., et al. (2019) Bortezomib Administered Prior to Temozolomide Depletes MGMT, Chemosensitizes Glioblastoma with Unmethylated MGMT Promoter and Prolongs Animal Survival. British Journal of Cancer, 121, 545-555. [Google Scholar] [CrossRef] [PubMed]
[39] Gras Navarro, A., Espedal, H., Joseph, J., Trachsel-Moncho, L., Bahador, M., Tore Gjertsen, B., et al. (2019) Pretreatment of Glioblastoma with Bortezomib Potentiates Natural Killer Cell Cytotoxicity through TRAIL/DR5 Mediated Apoptosis and Prolongs Animal Survival. Cancers, 11, Article 996. [Google Scholar] [CrossRef] [PubMed]
[40] Wang, W., Cho, H., Rosenstein-Sisson, R., Marín Ramos, N.I., Price, R., Hurth, K., et al. (2018) Intratumoral Delivery of Bortezomib: Impact on Survival in an Intracranial Glioma Tumor Model. Journal of Neurosurgery, 128, 695-700. [Google Scholar] [CrossRef] [PubMed]
[41] Nam, J.Y. and de Groot, J.F. (2017) Treatment of Glioblastoma. Journal of Oncology Practice, 13, 629-638. [Google Scholar] [CrossRef] [PubMed]
[42] Cabrini, G., Fabbri, E., Nigro, C.L., Dechecchi, M.C. and Gambari, R. (2015) Regulation of Expression of O6-Methylguanine-Dna Methyltransferase and the Treatment of Glioblastoma (Review). International Journal of Oncology, 47, 417-428. [Google Scholar] [CrossRef] [PubMed]
[43] Mansouri, A., Hachem, L.D., Mansouri, S., Nassiri, F., Laperriere, N.J., Xia, D., et al. (2018) MGMT Promoter Methylation Status Testing to Guide Therapy for Glioblastoma: Refining the Approach Based on Emerging Evidence and Current Challenges. Neuro-Oncology, 21, 167-178. [Google Scholar] [CrossRef] [PubMed]
[44] Bota, D.A., Mason, W., Kesari, S., Magge, R., Winograd, B., Elias, I., et al. (2021) Marizomib Alone or in Combination with Bevacizumab in Patients with Recurrent Glioblastoma: Phase I/II Clinical Trial Data. Neuro-Oncology Advances, 3, vdab142. [Google Scholar] [CrossRef] [PubMed]
[45] Manton, C.A., Johnson, B., Singh, M., Bailey, C.P., Bouchier-Hayes, L. and Chandra, J. (2016) Induction of Cell Death by the Novel Proteasome Inhibitor Marizomib in Glioblastoma in Vitro and in Vivo. Scientific Reports, 6, Article No. 18953. [Google Scholar] [CrossRef] [PubMed]
[46] Manu, K., Cao, P., Chai, T., Casey, P. and Wang, M. (2019) P21cip1/waf1 Coordinates Autophagy, Proliferation and Apoptosis in Response to Metabolic Stress. Cancers, 11, Article 1112. [Google Scholar] [CrossRef] [PubMed]
[47] Di, K., Lloyd, G.K., Abraham, V., MacLaren, A., Burrows, F.J., Desjardins, A., et al. (2015) Marizomib Activity as a Single Agent in Malignant Gliomas: Ability to Cross the Blood-Brain Barrier. Neuro-Oncology, 18, 840-848. [Google Scholar] [CrossRef] [PubMed]
[48] Boccellato, C., Kolbe, E., Peters, N., Juric, V., Fullstone, G., Verreault, M., et al. (2021) Marizomib Sensitizes Primary Glioma Cells to Apoptosis Induced by a Latest-Generation TRAIL Receptor Agonist. Cell Death & Disease, 12, Article No. 647. [Google Scholar] [CrossRef] [PubMed]