Synergistic Effect of β-Lapachone and Aminooxyacetic Acid on Central Metabolism in Breast Cancer.
Synergistic Effect of β-Lapachone and Aminooxyacetic Acid on Central Metabolism in Breast Cancer.
复制标题
β-拉帕酮和氨氧乙酸对乳腺癌中枢代谢的协同作用。
DOI：
10.3390/nu14153020
复制
发表时间：
2022-07-22
期刊：
影响因子：
5.9
通讯作者：
Merritt, Matthew E.
中科院分区：
文献类型：
--
作者：
Chang, Mario C.;Mahar, Rohit;McLeod, Marc A.;Giacalone, Anthony G.;Huang, Xiumei;Boothman, David A.;Merritt, Matthew E.
化合物β-拉帕醌是一种天然衍生的萘醌，已被用作改善健康的有效药用营养素。在过去的十二年中，许多报道已经证明β-拉帕醌和NAD（P）H：醌氧化还原酶1（NQO 1）蛋白在改善各种疾病中的明显关联。对NQO 1生物活性的全面研究已经清楚地证实了β-拉帕酮通过NAD+-电泳的杀肿瘤作用，其中活性氧（ROS）产生的严重DNA损伤触发聚ADP-核糖聚合酶-I（PARP 1）超活化级联，最终导致NAD+/ATP耗尽。在这里，我们报告了一种与氨基氧乙酸（AOA）的新型联合策略，AOA是一种天冬氨酸转氨酶抑制剂，可阻断苹果酸-天冬氨酸穿梭（MAS）并协同增强β-拉帕醌代谢扰动在NQO 1+乳腺癌中的疗效。我们通过测量来自[U-13 C]葡萄糖示踪剂的代谢物的同位素标记来评估MDA-MB-231 NQO 1+、MDA-MB-231 NQO 1 −、MDA-MB-468和T47 D癌细胞中的代谢周转。我们表明，β-拉帕醌处理显著阻碍NQO 1+细胞中乳酸分泌约85%。我们的数据表明，组合处理使柠檬酸盐、谷氨酸盐和琥珀酸盐的富集分别降低约14%、约50%和约65%。柠檬酸盐、谷氨酸盐和琥珀酸盐部分富集的差异表明基于药物相互作用系数对中枢代谢的协同作用。代谢模型表明，在MAS抑制的情况下，谷氨酰胺回补增加具有保护作用。
The compound β-lapachone, a naturally derived naphthoquinone, has been utilized as a potent medicinal nutrient to improve health. Over the last twelve years, numerous reports have demonstrated distinct associations of β-lapachone and NAD(P)H: quinone oxidoreductase 1 (NQO1) protein in the amelioration of various diseases. Comprehensive research of NQO1 bioactivity has clearly confirmed the tumoricidal effects of β-lapachone action through NAD+-keresis, in which severe DNA damage from reactive oxygen species (ROS) production triggers a poly-ADP-ribose polymerase-I (PARP1) hyperactivation cascade, culminating in NAD+/ATP depletion. Here, we report a novel combination strategy with aminooxyacetic acid (AOA), an aspartate aminotransferase inhibitor that blocks the malate-aspartate shuttle (MAS) and synergistically enhances the efficacy of β-lapachone metabolic perturbation in NQO1+ breast cancer. We evaluated metabolic turnover in MDA-MB-231 NQO1+, MDA-MB-231 NQO1−, MDA-MB-468, and T47D cancer cells by measuring the isotopic labeling of metabolites from a [U-13C]glucose tracer. We show that β-lapachone treatment significantly hampers lactate secretion by ~85% in NQO1+ cells. Our data demonstrate that combinatorial treatment decreases citrate, glutamate, and succinate enrichment by ~14%, ~50%, and ~65%, respectively. Differences in citrate, glutamate, and succinate fractional enrichments indicate synergistic effects on central metabolism based on the coefficient of drug interaction. Metabolic modeling suggests that increased glutamine anaplerosis is protective in the case of MAS inhibition.
登录
查看更多内容
影响因子：
50.3
作者：
Huang X;Motea EA;Moore ZR;Yao J;Dong Y;Chakrabarti G;Kilgore JA;Silvers MA;Patidar PL;Cholka A;Fattah F;Cha Y;Anderson GG;Kusko R;Peyton M;Yan J;Xie XJ;Sarode V;Williams NS;Minna JD;Beg M;Gerber DE;Bey EA;Boothman DA
通讯作者：
Boothman DA
影响因子：
3
作者：
Kim，Jin Hee;Lee，Se Mi;Hwang，Jae Sung
通讯作者：
Hwang，Jae Sung
影响因子：
5.7
作者：
Hong, Sun M.;Hwang, Sung W.;Choi, Kwan Y.
通讯作者：
Choi, Kwan Y.
影响因子：
5.5
作者：
Kung, Hsiu-Ni;Yang, Mei-Jun;Lu, Kuo-Shyan
通讯作者：
Lu, Kuo-Shyan
DOI：
10.1016/j.bbamcr.2016.04.011
发表时间：
2016-10-01
影响因子：
5.1
作者：
Amoedo, N. D.;Punzi, G.;Rossignol, R.
通讯作者：
Rossignol, R.