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Regulating tumor glycometabolism and the immune microenvironment by inhibiting lactate dehydrogenase with platinum(IV) complexes
Chemical Science ( IF 7.6 ) Pub Date : 2023-07-10 , DOI: 10.1039/d3sc01874a
Suxing Jin 1, 2 , Enmao Yin 1 , Chenyao Feng 1 , Yuewen Sun 1 , Tao Yang 3, 4 , Hao Yuan 3 , Zijian Guo 3, 4 , Xiaoyong Wang 1
Chemical Science ( IF 7.6 ) Pub Date : 2023-07-10 , DOI: 10.1039/d3sc01874a
Suxing Jin 1, 2 , Enmao Yin 1 , Chenyao Feng 1 , Yuewen Sun 1 , Tao Yang 3, 4 , Hao Yuan 3 , Zijian Guo 3, 4 , Xiaoyong Wang 1
Affiliation
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Lactate dehydrogenase (LDH) is a key enzyme involved in the process of glycolysis, assisting cancer cells to take in glucose and generate lactate, as well as to suppress and evade the immune system by altering the tumor microenvironment (TME). Platinum(IV) complexes MDP and DDP were prepared by modifying cisplatin with diclofenac at the axial position(s). These complexes exhibited potent antiproliferative activity against a panel of human cancer cell lines. In particular, DDP downregulated the expression of LDHA, LDHB, and MCTs to inhibit the production and influx/efflux of lactate in cancer cells, impeding both glycolysis and glucose oxidation. MDP and DDP also reduced the expression of HIF-1α, ARG1 and VEGF, thereby disrupting the formation of tumor vasculature. Furthermore, they promoted the repolarization of macrophages from the tumor-supportive M2 phenotype to the tumor-suppressive M1 phenotype in the TME, thus enhancing the antitumor immune response. The antitumor mechanism involves reprogramming the energy metabolism of tumor cells and relieving the immunosuppressive TME.
中文翻译：
通过铂(IV)络合物抑制乳酸脱氢酶调节肿瘤糖代谢和免疫微环境
乳酸脱氢酶（LDH）是参与糖酵解过程的关键酶，帮助癌细胞吸收葡萄糖并产生乳酸，并通过改变肿瘤微环境（TME）来抑制和逃避免疫系统。通过在轴向位置用双氯芬酸修饰顺铂制备铂( IV )配合物MDP和DDP。这些复合物对一组人类癌细胞系表现出有效的抗增殖活性。特别是，DDP 下调 LDHA、LDHB 和 MCT 的表达，从而抑制癌细胞中乳酸的产生和流入/流出，从而阻碍糖酵解和葡萄糖氧化。MDP和DDP还降低HIF-1α、ARG1和VEGF的表达，从而破坏肿瘤血管系统的形成。此外，它们促进TME中巨噬细胞从肿瘤支持性M2表型复极化为肿瘤抑制性M1表型，从而增强抗肿瘤免疫反应。抗肿瘤机制涉及重新编程肿瘤细胞的能量代谢和缓解免疫抑制性TME。
更新日期：2023-07-10
中文翻译：
通过铂(IV)络合物抑制乳酸脱氢酶调节肿瘤糖代谢和免疫微环境
乳酸脱氢酶（LDH）是参与糖酵解过程的关键酶，帮助癌细胞吸收葡萄糖并产生乳酸，并通过改变肿瘤微环境（TME）来抑制和逃避免疫系统。通过在轴向位置用双氯芬酸修饰顺铂制备铂( IV )配合物MDP和DDP。这些复合物对一组人类癌细胞系表现出有效的抗增殖活性。特别是，DDP 下调 LDHA、LDHB 和 MCT 的表达，从而抑制癌细胞中乳酸的产生和流入/流出，从而阻碍糖酵解和葡萄糖氧化。MDP和DDP还降低HIF-1α、ARG1和VEGF的表达，从而破坏肿瘤血管系统的形成。此外，它们促进TME中巨噬细胞从肿瘤支持性M2表型复极化为肿瘤抑制性M1表型，从而增强抗肿瘤免疫反应。抗肿瘤机制涉及重新编程肿瘤细胞的能量代谢和缓解免疫抑制性TME。
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