The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases.
The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases.
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DOI：
10.1126/sciadv.abg1964
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发表时间：
2021-11-05
期刊：
影响因子：
13.6
通讯作者：
Cerchietti L
中科院分区：
文献类型：
--
作者：
Marullo R;Castro M;Yomtoubian S;Calvo-Vidal MN;Revuelta MV;Krumsiek J;Cho A;Morgado PC;Yang S;Medina V;Roth BM;Bonomi M;Keshari KR;Mittal V;Navigante A;Cerchietti L
精氨酸通过抑制癌细胞的代谢来增强脑转移患者的放疗效果。选定的脑转移（BM）患者是放射治疗的候选者。 BM 中常见的泌乳代谢与放射抗性有关。我们证明 BM 表达一氧化氮 (NO) 合酶 2，并且给予其底物 L-精氨酸可降低 BM 患者的肿瘤乳酸。在一项安慰剂对照试验中，我们表明，在每次分次之前给予 L-精氨酸可以增强放射效果，改善 BM 的控制。临床前模型研究表明，L-精氨酸放射增敏是一种 NO 介导的机制，继发于癌细胞中诱导的代谢适应。我们发现肿瘤乳酸的减少是糖酵解减少的结果，糖酵解也影响了 ATP 和 NAD+ 水平。这些效应与亚硝化 DNA 损伤时 GAPDH 的 NO 依赖性抑制和 PARP 过度激活有关。这些代谢变化最终损害了癌细胞中辐射引起的 DNA 损伤的修复，同时极大地保护了肿瘤浸润淋巴细胞。
Arginine enhances the effect of radiation in patients with brain metastasis by metabolic suppression of cancer cells. Selected patients with brain metastases (BM) are candidates for radiotherapy. A lactatogenic metabolism, common in BM, has been associated with radioresistance. We demonstrated that BM express nitric oxide (NO) synthase 2 and that administration of its substrate l-arginine decreases tumor lactate in BM patients. In a placebo-controlled trial, we showed that administration of l-arginine before each fraction enhanced the effect of radiation, improving the control of BM. Studies in preclinical models demonstrated that l-arginine radiosensitization is a NO-mediated mechanism secondary to the metabolic adaptation induced in cancer cells. We showed that the decrease in tumor lactate was a consequence of reduced glycolysis that also impacted ATP and NAD+ levels. These effects were associated with NO-dependent inhibition of GAPDH and hyperactivation of PARP upon nitrosative DNA damage. These metabolic changes ultimately impaired the repair of DNA damage induced by radiation in cancer cells while greatly sparing tumor-infiltrating lymphocytes.
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影响因子：
168.9
作者：
DREXLER, H;ZEIHER, AM;JUST, H
通讯作者：
JUST, H
影响因子：
15.9
作者：
Glynn, Sharon A.;Boersma, Brenda J.;Ambs, Stefan
通讯作者：
Ambs, Stefan
DOI：
10.1016/s0360-3016(96)00329-x
发表时间：
1996-09-01
影响因子：
7
作者：
Griffin, RJ;Makepeace, CM;Song, CW
通讯作者：
Song, CW
DOI：
10.1016/0006-291x(80)91616-2
发表时间：
1980-01-01
影响因子：
3.1
作者：
CHOCHUNG, YS;CLAIR, T;HILL, DM
通讯作者：
HILL, DM
DOI：
10.1073/pnas.1401799111
发表时间：
2014-04-29
影响因子：
11.1
作者：
Heinecke, Julie L.;Ridnour, Lisa A.;Wink, David A.
通讯作者：
Wink, David A.