TIC10/ONC201 synergizes with Bcl-2/Bcl-xL inhibition in glioblastoma by suppression of Mcl-1 and its binding partners in vitro and in vivo.
TIC10/ONC201 synergizes with Bcl-2/Bcl-xL inhibition in glioblastoma by suppression of Mcl-1 and its binding partners in vitro and in vivo.
复制标题
DOI：
10.18632/oncotarget.5505
复制
发表时间：
2015-11-03
期刊：
影响因子：
--
通讯作者：
Siegelin MD
中科院分区：
文献类型：
--
作者：
Karpel-Massler G;Bâ M;Shu C;Halatsch ME;Westhoff MA;Bruce JN;Canoll P;Siegelin MD
胶质母细胞瘤是成人中最常见的原发性脑肿瘤。目前的治疗选择很少，患有这种疾病的患者的预后是严峻的。不同失调信号通路之间的肿瘤内异质性的减少是胶质母细胞瘤的标志，并可能解释其复发和对治疗的抗性。胶质母细胞瘤具有过多的驱动肿瘤形成和生长的失调途径。在这项研究中，我们表明，TIC 10/ONC 201，一个有前途的化合物，目前正在计划的临床开发，沿着Bcl-2/Bcl-xL抑制ABT 263产生了强大的协同抗增殖作用，对儿童，成人，前神经胶质母细胞瘤和神经胶质瘤干细胞样细胞。在分子水平上，用TIC 10/ONC 201治疗通过调节伴侣Bag 3和去泛素化酶Usp 9 X导致抗凋亡Bcl-2家族成员骨髓细胞白血病1（Mcl-1）的翻译后减少。一致地，TIC 10/ONC 201和ABT 263的组合治疗需要功能性BAX和巴克的存在以驱动内在凋亡，但令人惊讶地独立于外在凋亡途径。此外，Noxa蛋白的表达是TIC 10/ONC 201和ABT 263有效诱导细胞凋亡所必需的。重要的是，TIC 10/ONC 201和BH 3模拟物ABT 263的药物组合导致体内肿瘤消退，而没有任何显著的毒性和副作用。总体而言，TIC 10/ONC 201沿着Bcl-2/Bcl-xL抑制作为治疗恶性肿瘤如胶质母细胞瘤的新的潜在方法具有显著的前景。
Glioblastoma is the most frequent primary brain tumor in adults. Current therapeutic options are sparse and the prognosis of patients suffering from this disease is grim. Abundance in intratumoral heterogeneity among different deregulated signaling pathways is a hallmark of glioblastoma and likely accounts for its recurrence and resistance to treatment. Glioblastomas harbor a plethora of deregulated pathways driving tumor formation and growth. In this study, we show that TIC10/ONC201, a promising compound that is currently in planned clinical development, along with Bcl-2/Bcl-xL inhibition by ABT263 yields a strong synergistic antiproliferative effect on pediatric, adult, proneural glioblastoma and glioma stem-like cells. On the molecular level, treatment with TIC10/ONC201 results in a posttranslational decrease of the anti-apoptotic Bcl-2 family member, myeloid cell leukemia 1 (Mcl-1), through modulation of the chaperone Bag3 and the deubiquitinase Usp9X. Consistently, the combination treatment of TIC10/ONC201 and ABT263 required the presence of functional BAX and BAK to drive intrinsic apoptosis, but is surprisingly independent of the extrinsic apoptotic pathway. Moreover, the expression of Noxa protein was required for efficient apoptosis induction by TIC10/ONC201 and ABT263. Importantly, the drug combination of TIC10/ONC201 and the BH3-mimetic, ABT263, led to a regression of tumors in vivo, without any notable toxicity and side effects. Overall, TIC10/ONC201 along with Bcl-2/Bcl-xL inhibition holds significant promise as a novel potential approach for the treatment of recalcitrant tumors such as glioblastoma.