Wang Ziyu, Xie Qinghong, Zhou Haifeng, Zhang Min, Shen Jie, Ju Dianwen
Department of Pharmacy, Huadong Hospital, Fudan University, Shanghai, China.
Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, Shanghai, China.
Front Pharmacol. 2021 Jan 11;11:582587. doi: 10.3389/fphar.2020.582587. eCollection 2020.
Recently, there has been renewed interest in metabolic therapy for cancer, particularly in amino acid deprivation by enzymes. L-asparaginase was approved for the treatment of acute lymphoblastic leukemia by the U.S. Food and Drug Administration. Arginine deiminase and recombinant human arginase have been developed into clinical trials as potential cancer therapeutic agents for the treatment of arginine-auxotrophic tumors. Moreover, other novel amino acid degrading enzymes, such as glutaminase, methionase, lysine oxidase, phenylalanine ammonia lyase, have been developed for the treatment of malignant cancers. One of the greatest obstacles faced by anticancer drugs is the development of drug resistance, which is reported to be associated with autophagy. Autophagy is an evolutionarily conserved catabolic process that is responsible for the degradation of dysfunctional proteins and organelles. There is a growing body of literature revealing that, in response to metabolism stress, autophagy could be induced by amino acid deprivation. The manipulation of autophagy in combination with amino acid degrading enzymes is actively being investigated as a potential therapeutic approach in preclinical studies. Importantly, shedding light on how autophagy fuels tumor metabolism during amino acid deprivation will enable more potential combinational therapeutic strategies. This study summarizes recent advances, discussing several potential anticancer enzymes, and highlighting the promising combined therapeutic strategy of amino acid degrading enzymes and autophagy modulators in tumors.
最近，人们对癌症的代谢疗法重新产生了兴趣，尤其是通过酶进行氨基酸剥夺。L-天冬酰胺酶已被美国食品药品监督管理局批准用于治疗急性淋巴细胞白血病。精氨酸脱亚氨酶和重组人精氨酸酶已进入临床试验，作为治疗精氨酸营养缺陷型肿瘤的潜在癌症治疗药物。此外，其他新型氨基酸降解酶，如谷氨酰胺酶、蛋氨酸酶、赖氨酸氧化酶、苯丙氨酸解氨酶，也已被开发用于治疗恶性肿瘤。抗癌药物面临的最大障碍之一是耐药性的产生，据报道这与自噬有关。自噬是一种进化上保守的分解代谢过程，负责降解功能失调的蛋白质和细胞器。越来越多的文献表明，在代谢应激反应中，氨基酸剥夺可诱导自噬。在临床前研究中，将自噬与氨基酸降解酶联合应用作为一种潜在的治疗方法正在积极研究中。重要的是，阐明自噬在氨基酸剥夺期间如何促进肿瘤代谢将有助于开发更多潜在的联合治疗策略。本研究总结了近期进展，讨论了几种潜在的抗癌酶，并强调了氨基酸降解酶和自噬调节剂在肿瘤中具有前景的联合治疗策略。
