Advancing Cancer Treatment by Targeting Glutamine Metabolism-A Roadmap.
Advancing Cancer Treatment by Targeting Glutamine Metabolism-A Roadmap.
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DOI：
10.3390/cancers14030553
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发表时间：
2022-01-22
期刊：
影响因子：
5.2
通讯作者：
Suhre K
中科院分区：
文献类型：
--
作者：
Halama A;Suhre K
与正常细胞相比，谷氨酰胺代谢失调是癌细胞中明显的代谢特征之一。癌细胞利用谷氨酰胺产生能量以及合成对癌症生长和进展至关重要的其他分子。因此，针对谷氨酰胺代谢的药物已被广泛研究。然而，抑制癌细胞中的谷氨酰胺代谢导致其他代谢途径的激活，使癌细胞能够存活。本文就谷氨酰胺代谢的靶点及其在抗肿瘤药物开发中的应用进行综述。我们进一步讨论了响应谷氨酰胺代谢抑制而激活的途径，使癌细胞能够在挑战中存活。最后，我们将谷氨酰胺代谢沿着其他途径作为潜在的治疗选择纳入联合治疗策略。肿瘤生长和转移强烈依赖于适应性细胞代谢。癌细胞调整其代谢程序以适应其特定的能量需求，并应对经常具有挑战性的肿瘤微环境。谷氨酰胺代谢是可以成功靶向治疗癌症的代谢途径之一。许多血液肿瘤和实体瘤对谷氨酰胺的依赖性与线粒体谷氨酰胺酶（GLS）活性相关，该活性使谷氨酰胺进入三羧酸（TCA）循环，生成ATP和NADPH，并调节谷胱甘肽稳态和活性氧（ROS）。因此，通过抑制GLS靶向谷氨酰胺代谢的小分子同时限制能量可用性并增加氧化应激。然而，一些癌症可以重新编程其代谢以逃避这种代谢陷阱。因此，仅依赖于谷氨酰胺抑制的治疗策略的有效性是有限的。在这篇综述中，我们讨论了与多种癌症类型中谷氨酰胺代谢失调有关的代谢和分子途径。我们进一步总结和审查目前的临床试验，在癌症患者中的氨解抑制。最后，我们提出了前瞻性的策略，部署一个联合治疗靶向谷氨酰胺代谢沿着与其他分子或代谢途径，并讨论其潜在的临床应用。
Dysregulated glutamine metabolism is one of the metabolic features evident in cancer cells when compared to normal cells. Cancer cells utilize glutamine for energy generation as well as the synthesis of other molecules that are critical for cancer growth and progression. Therefore, drugs targeting glutamine metabolism have been extensively investigated. However, inhibition of glutamine metabolism in cancer cells results in the activation of other metabolic pathways enabling cancer cells to survive. In this review, we summarize and discuss the targets in glutamine metabolism, which has been probed in the development of anticancer drugs in preclinical and clinical studies. We further discuss pathways activated in response to glutamine metabolism inhibition, enabling cancer cells to survive the challenge. Finally, we put into perspective combined treatment strategies targeting glutamine metabolism along with other pathways as potential treatment options. Tumor growth and metastasis strongly depend on adapted cell metabolism. Cancer cells adjust their metabolic program to their specific energy needs and in response to an often challenging tumor microenvironment. Glutamine metabolism is one of the metabolic pathways that can be successfully targeted in cancer treatment. The dependence of many hematological and solid tumors on glutamine is associated with mitochondrial glutaminase (GLS) activity that enables channeling of glutamine into the tricarboxylic acid (TCA) cycle, generation of ATP and NADPH, and regulation of glutathione homeostasis and reactive oxygen species (ROS). Small molecules that target glutamine metabolism through inhibition of GLS therefore simultaneously limit energy availability and increase oxidative stress. However, some cancers can reprogram their metabolism to evade this metabolic trap. Therefore, the effectiveness of treatment strategies that rely solely on glutamine inhibition is limited. In this review, we discuss the metabolic and molecular pathways that are linked to dysregulated glutamine metabolism in multiple cancer types. We further summarize and review current clinical trials of glutaminolysis inhibition in cancer patients. Finally, we put into perspective strategies that deploy a combined treatment targeting glutamine metabolism along with other molecular or metabolic pathways and discuss their potential for clinical applications.
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影响因子：
11.2
作者：
Cui, Hongyan;Darmanin, Stephanie;Kobayashi, Masanobu
通讯作者：
Kobayashi, Masanobu
影响因子：
7.3
作者：
Coothankandaswamy, V.;Cao, S.;Bhutia, Y. D.
通讯作者：
Bhutia, Y. D.
影响因子：
4.6
作者：
Chen, Bing-Huei;Hsieh, Chia-Hung;Wang, Chi-Chung
通讯作者：
Wang, Chi-Chung
影响因子：
3.1
作者：
AUSPRUNK, DH;FOLKMAN, J
通讯作者：
FOLKMAN, J
影响因子：
4.8
作者：
Broer, Angelika;Gauthier-Coles, Gregory;Broer, Stefan
通讯作者：
Broer, Stefan