Visualizing the effects of lactate dehydrogenase (LDH) inhibition and LDH-A genetic ablation in breast and lung cancer with hyperpolarized pyruvate NMR.
Visualizing the effects of lactate dehydrogenase (LDH) inhibition and LDH-A genetic ablation in breast and lung cancer with hyperpolarized pyruvate NMR.
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DOI：
10.1002/nbm.4560
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发表时间：
2021-08
影响因子：
2.9
通讯作者：
Grant AK
中科院分区：
文献类型：
--
作者：
Varma G;Seth P;Coutinho de Souza P;Callahan C;Pinto J;Vaidya M;Sonzogni O;Sukhatme V;Wulf GM;Grant AK
在许多肿瘤中，癌细胞吸收大量的葡萄糖并将其代谢成乳酸，即使在有足够的氧气支持氧化代谢的情况下也是如此。据推测，这种恶性代谢表型支持癌症的生长和转移，这种所谓的“华宝效应”的逆转可能会选择性地损害癌细胞。葡萄糖到乳酸的转化可以通过去除或抑制乳酸脱氢酶(LDH)来减少，乳酸脱氢酶负责在糖酵解的终点将丙酮酸转化为乳酸。最近开发的乳酸脱氢酶抑制剂为研究这一代谢途径在癌症中的作用提供了新的机会。在这里，我们展示了超极化的丙酮酸及其代谢产物在乳腺癌和肺癌模型中的磁共振光谱成像(MRSI)显示，LDH的抑制很容易通过减少丙酮酸和乳酸之间的标记交换而被可视化，而单独的遗传消融LDH-A亚型的影响较小。在乳腺癌LDH抑制的急性期，未观察到明显的碳酸氢盐信号，丙氨酸的小信号没有变化。利用超极化~(13)C-丙酮酸核磁共振成像(MRSI)研究乳腺癌和肺癌模型中LDH抑制后的代谢途径，以及后者的LDH-A基因消融。·药物GNOE-140抑制LDH后，MRSI显示超极化丙酮酸和乳酸之间的标记交换持续减少。·他莫昔芬单独诱导的LDH-A亚型缺失在超极化的丙酮酸到乳酸的交换中显示出轻微的、不显著的减少。
In many tumors, cancer cells take up large quantities of glucose and metabolize it into lactate, even in the presence of sufficient oxygen to support oxidative metabolism. It has been hypothesized that this malignant metabolic phenotype supports cancer growth and metastasis, and that reversal of this so-called ‘Warburg effect’ may selectively harm cancer cells. Conversion of glucose to lactate can be reduced by ablation or inhibition of lactate dehydrogenase (LDH), the enzyme responsible for conversion of pyruvate to lactate at the endpoint of glycolysis. Recently developed inhibitors of lactate dehydrogenase provide new opportunities to investigate the role of this metabolic pathway in cancer. Here we show that magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized pyruvate and its metabolites in models of breast and lung cancer revealed that inhibition of LDH was readily visualized through reduction in label exchange between pyruvate and lactate, while genetic ablation of the LDH-A isoform alone had smaller effects. During the acute phase of LDH inhibition in breast cancer, no discernible bicarbonate signal was observed and small signals from alanine were unchanged. • Hyperpolarized 13C pyruvate magnetic resonance spectroscopic imaging (MRSI) was used to investigate the metabolic pathway following LDH inhibition in models of breast and lung cancer, as well as LDH-A genetic ablation in the latter. • A consistent reduction in label exchange between hyperpolarized pyruvate and lactate was visualized by MRSI following LDH inhibition by the drug GNE-140. • Tamoxifen-induced deletion of the LDH-A isoform alone showed a small, non-significant reduction in hyperpolarized pyruvate to lactate exchange.
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影响因子：
3.7
作者：
Regales L;Balak MN;Gong Y;Politi K;Sawai A;Le C;Koutcher JA;Solit DB;Rosen N;Zakowski MF;Pao W
通讯作者：
Pao W
影响因子：
7.2
作者：
Husain Z;Seth P;Sukhatme VP
通讯作者：
Sukhatme VP
影响因子：
11.2
作者：
Dutta P;Le A;Vander Jagt DL;Tsukamoto T;Martinez GV;Dang CV;Gillies RJ
通讯作者：
Gillies RJ
影响因子：
4.8
作者：
Seth, Pankaj;Grant, Aaron;Sukhatme, Vikas P.
通讯作者：
Sukhatme, Vikas P.
影响因子：
2.9
作者：
Chen, Hsin-Yu;Gordon, Jeremy W.;Larson, Peder E. Z.
通讯作者：
Larson, Peder E. Z.