Pediatric and adult glioblastoma radiosensitization induced by PI3K/mTOR inhibition causes early metabolic alterations detected by nuclear magnetic resonance spectroscopy.
Pediatric and adult glioblastoma radiosensitization induced by PI3K/mTOR inhibition causes early metabolic alterations detected by nuclear magnetic resonance spectroscopy.
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由PI3K/MTOR抑制引起的小儿和成人胶质母细胞瘤放射素化导致核磁共振光谱检测到的早期代谢改变。
DOI：
10.18632/oncotarget.18206
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发表时间：
2017-07-18
期刊：
影响因子：
--
通讯作者：
Al-Saffar NMS
中科院分区：
文献类型：
--
作者：
Agliano A;Balarajah G;Ciobota DM;Sidhu J;Clarke PA;Jones C;Workman P;Leach MO;Al-Saffar NMS
胶质母细胞瘤患者的不良预后通常与放射抵抗有关。PI 3 K/mTOR通路失调与放射抗性相关;因此，PI 3 K/mTOR抑制可使肿瘤对放射敏感。在这项研究中，我们表明NVP-BEZ 235，一种双重PI 3 K/mTOR抑制剂，增强了成人和儿童胶质母细胞瘤细胞系的辐射效应，导致通过核磁共振（NMR）光谱检测到的早期代谢变化。NVP-BEZ 235使细胞对X射线照射敏感，通过抑制CDC 25 A和激活p21 cip 1（CDKN 1A）诱导细胞死亡。乳酸盐和磷酸胆碱水平随辐射增加，在NVP-BEZ 235和组合治疗后降低，表明抑制PI 3 K/mTOR途径逆转辐射诱导的代谢变化。重要的是，NVP-BEZ 235增强了成人胶质母细胞瘤异种移植模型中的辐射效应，在该模型中，我们观察到联合治疗7天后乳酸和磷酸胆碱水平降低。尽管由于治疗时间短，肿瘤大小未受影响，但在联合治疗组中观察到CASP 3 mRNA显著增加。总而言之，我们的数据表明，核磁共振代谢物可用作生物标志物，以检测成人和儿童胶质母细胞瘤患者对PI 3 K/mTOR抑制剂和放疗联合治疗的早期反应。
Poor outcome for patients with glioblastomas is often associated with radioresistance. PI3K/mTOR pathway deregulation has been correlated with radioresistance; therefore, PI3K/mTOR inhibition could render tumors radiosensitive. In this study, we show that NVP-BEZ235, a dual PI3K/mTOR inhibitor, potentiates the effects of irradiation in both adult and pediatric glioblastoma cell lines, resulting in early metabolic changes detected by nuclear magnetic resonance (NMR) spectroscopy. NVP-BEZ235 radiosensitises cells to X ray exposure, inducing cell death through the inhibition of CDC25A and the activation of p21cip1(CDKN1A). Lactate and phosphocholine levels, increased with radiation, are decreased after NVP-BEZ235 and combination treatment, suggesting that inhibiting the PI3K/mTOR pathway reverses radiation induced metabolic changes. Importantly, NVP-BEZ235 potentiates the effects of irradiation in a xenograft model of adult glioblastoma, where we observed a decrease in lactate and phosphocholine levels after seven days of combination treatment. Although tumor size was not affected due to the short length of the treatment, a significant increase in CASP3 mRNA was observed in the combination group. Taken together, our data suggest that NMR metabolites could be used as biomarkers to detect an early response to combination therapy with PI3K/mTOR inhibitors and radiotherapy in adult and pediatric glioblastoma patients.
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影响因子：
5.7
作者：
Beloueche-Babari, M;Jackson, LE;Ronen, SM
通讯作者：
Ronen, SM
影响因子：
2.6
作者：
Hazawa M;Yasuda T;Noshiro K;Saotome-Nakamura A;Fukuzaki T;Michikawa Y;Gotoh T;Tajima K
通讯作者：
Tajima K
DOI：
10.1158/1078-0432.ccr-13-1607
发表时间：
2014-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Gil del Alcazar CR;Hardebeck MC;Mukherjee B;Tomimatsu N;Gao X;Yan J;Xie XJ;Bachoo R;Li L;Habib AA;Burma S
通讯作者：
Burma S
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
56.9
作者：
Bunz, F;Dutriaux, A;Vogelstein, B
通讯作者：
Vogelstein, B