Vasileva N S, Ageenko A B, Richter V A, Kuligina E V
Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, 630090 Russia.
Acta Naturae. 2022 Apr-Jun;14(2):62-70. doi: 10.32607/actanaturae.11623.
The resistance of glioblastoma to existing therapies puts limits on quality-of-life improvements and patient survival with a glioblastoma diagnosis. The development of new effective glioblastoma therapies is based on knowledge about the mechanisms governing tumor resistance to therapeutic agents. Virotherapy is one of the most actively developing approaches to the treatment of malignant neoplasms: glioblastoma in particular. Previously, we demonstrated that the recombinant vaccinia virus VV-GMCSF-Lact exhibits cytotoxic activity and antitumor efficacy against human glioblastoma. However, the studied glioblastoma cell cultures had different sensitivities to the oncotoxic effect of the virus. In this study, we investigated cancer stem cell (CSC) surface markers in glioblastoma cells with different sensitivities to VV-GMCSFLact using flow cytometry and we assessed the levels of proteins affecting viral entry into cells and virus infection efficiency by western blotting. We showed that cell cultures more sensitive to VV-GMCSF-Lact are characterized by a greater number of cells with CSC markers and a lower level of activated Akt kinase. Akt probably inhibits lactaptin-induced apoptosis in virus-resistant cells. Hence, we suggest that the sensitivity of glioblastoma cells to the oncotoxic effect of VV-GMCSF-Lact is determined by the nature and extent of the disturbances in cell death regulation in various cultures. Further investigation of the factors affecting glioblastoma resistance to virotherapy will test this hypothesis and identify targets for antitumor therapy, combined with VV-GMCSF-Lact.
胶质母细胞瘤对现有疗法的耐药性限制了胶质母细胞瘤患者生活质量的改善和生存期。新型有效胶质母细胞瘤疗法的开发基于对肿瘤对治疗药物耐药机制的了解。病毒疗法是治疗恶性肿瘤(尤其是胶质母细胞瘤)最积极发展的方法之一。此前,我们证明重组痘苗病毒VV-GMCSF-Lact对人胶质母细胞瘤具有细胞毒性活性和抗肿瘤功效。然而,所研究的胶质母细胞瘤细胞培养物对该病毒的致癌毒性作用具有不同的敏感性。在本研究中,我们使用流式细胞术研究了对VV-GMCSF-Lact具有不同敏感性的胶质母细胞瘤细胞中的癌症干细胞(CSC)表面标志物,并通过蛋白质印迹法评估了影响病毒进入细胞和病毒感染效率的蛋白质水平。我们发现,对VV-GMCSF-Lact更敏感的细胞培养物的特征是具有CSC标志物的细胞数量更多,且活化的Akt激酶水平较低。Akt可能抑制了病毒抗性细胞中乳清蛋白诱导的细胞凋亡。因此,我们认为胶质母细胞瘤细胞对VV-GMCSF-Lact致癌毒性作用的敏感性取决于不同培养物中细胞死亡调控紊乱的性质和程度。对影响胶质母细胞瘤对病毒疗法耐药性的因素进行进一步研究将验证这一假设,并确定与VV-GMCSF-Lact联合使用的抗肿瘤治疗靶点。