The natural compound obtusaquinone targets pediatric high-grade gliomas through ROS-mediated ER stress.
The natural compound obtusaquinone targets pediatric high-grade gliomas through ROS-mediated ER stress.
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DOI：
10.1093/noajnl/vdaa106
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发表时间：
2020-01
期刊：
影响因子：
--
通讯作者：
Tannous BA
中科院分区：
文献类型：
--
作者：
Teng J;Lashgari G;Tabet EI;Tannous BA
儿童高级别胶质瘤 (pHGG) 是一种侵袭性原发性脑肿瘤，具有局部侵袭性生长和不良的临床预后。鉴于对化疗的内在耐药性、缺乏新的治疗方法以及药物难以到达肿瘤床，pHGG 的治疗尤其具有挑战性。越来越多的证据表明，活性氧（ROS）和错误折叠蛋白质的产生通常会导致内质网（ER）应激，是癌细胞存活的重要机制。在 6 例患者来源的 pHGG 培养物中进行了多种细胞活力测定，以评估天然化合物 obtusaquinone (OBT) 对细胞毒性的影响。原位小鼠模型用于确定体内 OBT 效果。使用免疫印迹、免疫染色、流式细胞术和生化分析来研究 OBT 的作用机制。 OBT 显着抑制培养物中患者来源的 pHGG 细胞的细胞存活。 OBT 在 2 种不同的原位异种移植模型中抑制肿瘤生长并延长生存期。从机制上讲，OBT 通过异常的 ROS 积累诱导 ER 应激。我们的数据证明了 OBT 作为改善 pHGG 临床治疗的潜在治疗选择的实用性和可行性。
Pediatric high-grade gliomas (pHGGs) are aggressive primary brain tumors with local invasive growth and poor clinical prognosis. Treatment of pHGGs is particularly challenging given the intrinsic resistance to chemotherapy, an absence of novel therapeutics, and the difficulty of drugs to reach the tumor beds. Accumulating evidence suggests that production of reactive oxygen species (ROS) and misfolded proteins, which typically leads to endoplasmic reticulum (ER) stress, is an essential mechanism in cancer cell survival. Several cell viability assays were used in 6 patient-derived pHGG cultures to evaluate the effect of the natural compound obtusaquinone (OBT) on cytotoxicity. Orthotopic mouse models were used to determine OBT effects in vivo. Immunoblotting, immunostaining, flow cytometry, and biochemical assays were used to investigate the OBT mechanism of action. OBT significantly inhibited cell survival of patient-derived pHGG cells in culture. OBT inhibited tumor growth and extended survival in 2 different orthotopic xenograft models. Mechanistically, OBT induced ER stress through abnormal ROS accumulation. Our data demonstrate the utility and feasibility of OBT as a potential therapeutic option for improving the clinical treatment of pHGGs.
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影响因子：
3.7
作者：
Badr CE;Hewett JW;Breakefield XO;Tannous BA
通讯作者：
Tannous BA
影响因子：
12.7
作者：
Caretti V;Sewing AC;Lagerweij T;Schellen P;Bugiani M;Jansen MH;van Vuurden DG;Navis AC;Horsman I;Vandertop WP;Noske DP;Wesseling P;Kaspers GJ;Nazarian J;Vogel H;Hulleman E;Monje M;Wurdinger T
通讯作者：
Wurdinger T
影响因子：
8.4
作者：
Bailey, S.;Howman, A.;Hargrave, D.
通讯作者：
Hargrave, D.
影响因子：
64.5
作者：
Qin EY;Cooper DD;Abbott KL;Lennon J;Nagaraja S;Mackay A;Jones C;Vogel H;Jackson PK;Monje M
通讯作者：
Monje M
DOI：
10.1038/mt.2011.17
发表时间：
2011-06-01
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
Niers, Johanna M;Kerami, Mariam;Tannous, Bakhos A
通讯作者：
Tannous, Bakhos A