Despite decades of research and numerous basic science advances, there have only marginal gains in improving glioblastoma multiforme survival. Therefore, new ideas and approaches for treating this aggressive disease are essential to drive progress forward. Conventional therapies, such as radiation and Temozolomide (TMZ), function to cause oxidative stress and DNA damage yielding a senescent-like state of replicative arrest in susceptible cells. However, increasing evidence demonstrates malignant cells can escape senescence leading to tumor recurrence. Ablation of non-replicating senescent tumor cells after radiation and chemotherapy may be an avenue to reduce the rates of tumor recurrence. Senolytic agents have been developed that selectively target senescent cells, but it remains unknown whether senolytics might be utilized against senescent-like glioma cells. We employed radiation or TMZ to induce a functionally senescent state in human glioblastoma cells. Viable cells that survive these treatments were then utilized to screen candidate senolytic drugs, to identify those selectively effective at ablating senescent-like cells over na&iumlve non-tumor and proliferative cells. Among 10 candidate senolytic drugs evaluated, only Bcl-XL inhibitors demonstrated reproducible senolytic activity in radiated or TMZ-treated glioma across the majority of GBM cell lines evaluated. Conversely, Bcl-2 inhibitors and other established senolytic drugs failed to show any consistent senolytic activity. In agreement with these data, Bcl-XL knockdown selectively reduced the viability of senescent-like GBM cells, whereas knockdown of Bcl-2 or Bcl-W yielded no senolytic effect. These findings demonstrate the potential to harness radiation-induced biology to ablate latent surviving cells and highlight Bcl-XL dependency as a potential vulnerability of surviving GBM cells after exposure to radiation or TMZ.

中文翻译：

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衰老的胶质母细胞瘤细胞对Bcl-XL抑制的选择性脆弱性

尽管进行了数十年的研究并获得了许多基础科学方面的进步，但是改善胶质母细胞瘤多形体的存活率仅取得了很小的进展。因此，治疗这种侵袭性疾病的新思路和方法对于推动进步至关重要。常规疗法，例如放射疗法和替莫唑胺（TMZ），可引起氧化应激和DNA损伤，从而在易感细胞中产生衰老状的复制停滞状态。然而，越来越多的证据表明，恶性细胞可以逃脱衰老，导致肿瘤复发。放疗和化疗后消融未复制的衰老肿瘤细胞可能是降低肿瘤复发率的途径。已开发出选择性靶向衰老细胞的骨溶解剂，但是尚不清楚是否可以使用senolytics来对抗衰老样神经胶质瘤细胞。我们采用辐射或TMZ诱导人胶质母细胞瘤细胞功能性衰老。在这些治疗中存活的活细胞然后被用来筛选候选的抗衰老药物，以鉴定那些选择性地消融衰老样细胞而不是幼稚的非肿瘤和增生细胞的细胞。在评估的10种候选镇静药物中，只有Bcl-XL抑制剂在大多数评估的GBM细胞系中在放疗或TMZ处理的神经胶质瘤中显示出可再现的镇静活性。相反，Bcl-2抑制剂和其他已建立的衰老药未能显示出任何一致的衰老活性。与这些数据相吻合，Bcl-XL抑制可选择性降低衰老样GBM细胞的活力，而敲除Bcl-2或Bcl-W则没有衰老作用。这些发现证明了利用辐射诱导的生物学消融潜伏的存活细胞的潜力，并强调了Bcl-XL依赖性是暴露于放射线或TMZ后存活的GBM细胞的潜在脆弱性。