Ammour Yulia, Nikolaeva Eugenia, Sagimbaeva Olesya, Shamsutdinov Pavel, Astapenko Anastasia, Zhelaeva Yulia, Gavrilova Marina, Susova Olga, Mitrofanov Aleksey, Bekyashev Ali, Nasedkina Tatiana, Svitich Oxana, Faizuloev Evgeny, Zverev Vitaly
I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia.
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
Viruses. 2024 Dec 19;16(12):1944. doi: 10.3390/v16121944.
This study evaluates the oncolytic potential of the Moscow strain of reovirus against human metastatic melanoma and glioblastoma cells. The Moscow strain effectively infects and replicates within human melanoma cell lines and primary glioblastoma cells, while sparing non-malignant human cells. Infection leads to the selective destruction of neoplastic cells, mediated by functional viral replication. A positive correlation was identified between viral RNA accumulation and tumor cell death, with no replication observed in non-malignant cells. This study highlights the critical roles of cathepsins B, L, and S as mediators of the oncolytic process. The pharmacological inhibition of these enzymes significantly attenuated reovirus-induced cytotoxicity in melanoma and glioblastoma cells. Conversely, PKR production analysis revealed minimal activation in reovirus-infected tumor cells, suggesting that the hyperactivation of the RAS-signaling pathway and subsequent PKR inhibition do not directly contribute to the selective efficacy of reovirus. Moreover, infected tumor cells exhibited features of both apoptotic and non-apoptotic death, emphasizing the intricate mechanisms of reovirus-mediated oncolysis. These findings underscore the therapeutic promise of the Moscow strain of reovirus as a selective and potent oncolytic agent for targeting melanoma and glioblastoma cells.
本研究评估了呼肠孤病毒莫斯科株对人转移性黑色素瘤细胞和胶质母细胞瘤细胞的溶瘤潜力。莫斯科株能有效感染人黑色素瘤细胞系和原发性胶质母细胞瘤细胞并在其中复制，同时不影响非恶性人细胞。感染导致肿瘤细胞被选择性破坏，这是由功能性病毒复制介导的。病毒RNA积累与肿瘤细胞死亡之间存在正相关，在非恶性细胞中未观察到复制现象。本研究强调了组织蛋白酶B、L和S作为溶瘤过程介质的关键作用。对这些酶的药理学抑制显著减弱了呼肠孤病毒在黑色素瘤和胶质母细胞瘤细胞中诱导的细胞毒性。相反，PKR产生分析显示呼肠孤病毒感染的肿瘤细胞中激活程度最低，这表明RAS信号通路的过度激活及随后的PKR抑制并非呼肠孤病毒选择性疗效的直接原因。此外，受感染的肿瘤细胞表现出凋亡和非凋亡死亡的特征，强调了呼肠孤病毒介导的溶瘤作用的复杂机制。这些发现强调了呼肠孤病毒莫斯科株作为一种针对黑色素瘤和胶质母细胞瘤细胞的选择性强效溶瘤剂的治疗前景。
