Review

天冬氨酸：靶向肿瘤治疗中的关键代谢枢纽

Asparagine: A key metabolic junction in targeted tumor therapy

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PHARMACOLOGICAL RESEARCH

影响因子:10.5

分区:医学2区 Top / 药学1区

发表日期:2024 Aug

作者: Xuan Wang, Weijian Gong, Xueyou Xiong, Xuemei Jia, Juan Xu

DOI: 10.1016/j.phrs.2024.107292

摘要

肿瘤微环境中的营养物质生物可利用性在肿瘤的增殖和转移中发挥着关键作用。在这些营养物质中，谷氨酰胺是一种促进肿瘤生长和增殖的关键物质，其下游代谢产物天冬氨酸在肿瘤中也具有重要作用。研究表明，当谷氨酰胺耗尽时，肿瘤细胞可以依赖天冬氨酸以维持其生长。鉴于肿瘤细胞增殖对天冬氨酸的依赖性，限制其生物可利用性已成为癌症治疗中的一项有前景的策略。例如，使用天冬氨酶（一种能耗尽天冬氨酸的酶）已成为急性淋巴细胞白血病（ALL）的一项关键化疗手段。然而，肿瘤细胞可以适应天冬氨酸限制，从而导致化疗效果下降，不同基因变异肿瘤对天冬氨酸限制的敏感性或适应机制各异。本文综述了天冬氨酸的来源，探讨限制其生物可利用性如何影响特定基因变异肿瘤的进展。希望通过靶向肿瘤适应天冬氨酸限制的信号通路及其相关因素，能够解决药物耐药问题。重要的是，这些策略为基因变异癌症提供了精准的治疗途径。

Abstract

Nutrient bioavailability in the tumor microenvironment plays a pivotal role in tumor proliferation and metastasis. Among these nutrients, glutamine is a key substance that promotes tumor growth and proliferation, and its downstream metabolite asparagine is also crucial in tumors. Studies have shown that when glutamine is exhausted, tumor cells can rely on asparagine to sustain their growth. Given the reliance of tumor cell proliferation on asparagine, restricting its bioavailability has emerged as promising strategy in cancer treatment. For instance, the use of asparaginase, an enzyme that depletes asparagine, has been one of the key chemotherapies for acute lymphoblastic leukemia (ALL). However, tumor cells can adapt to asparagine restriction, leading to reduced chemotherapy efficacy, and the mechanisms by which different genetically altered tumors are sensitized or adapted to asparagine restriction vary. We review the sources of asparagine and explore how limiting its bioavailability impacts the progression of specific genetically altered tumors. It is hoped that by targeting the signaling pathways involved in tumor adaptation to asparagine restriction and certain factors within these pathways, the issue of drug resistance can be addressed. Importantly, these strategies offer precise therapeutic approaches for genetically altered cancers.