Development of a novel lactate dehydrogenase A inhibitor with potent antitumor activity and immune activation
文献类型：期刊论文
| 作者 | Du, Mengyan1,2,3; Yu, Ting4; Zhan, Qinjinge5; Li, Han6; Zou, Yiping5; Geng, Meiyu1,2,3 ; Meng, Tao4; Xie, Zuoquan1,3
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| 刊名 | CANCER SCIENCE
 |
| 出版日期 | 2022-09 |
| 卷号 | 113期号:9页码:2974-2985 |
| 关键词 | immunity lactate LDHA inhibitor metabolic reprogramming tumor microenvironment |
| ISSN号 | 1347-9032 |
| DOI | 10.1111/cas.15468 |
| 文献子类 | Article |
| 英文摘要 | Lactate accumulation in the tumor microenvironment was shown to be closely related to tumor growth and immune escape, and suppression of lactate production by inhibiting lactate dehydrogenase A (LDHA) has been pursued as a potential novel antitumor strategy. However, only a few potent LDHA inhibitors have been developed and most of them did not show potent antitumor effects in vivo. To this end, we designed new LDHA inhibitors and obtained a novel potent LDHA inhibitor, ML-05. ML-05 inhibited cellular lactate production and tumor cell proliferation, which was associated with inhibition of ATP production and induction of reactive oxygen species and G(1) phase arrest. In a mouse B16F10 melanoma model, intratumoral injection of ML-05 significantly reduced lactate production, inhibited tumor growth, and released antitumor immune response of T cell subsets (Th1 and GMZB(+)CD8 T cells) in the tumor microenvironment. Moreover, ML-05 treatment combined with programmed cell death-1 Ab or stimulator of interferon genes protein (STING) could sensitize the antitumor activity in B16F10 melanoma model. Collectively, we developed a novel potent LDHA inhibitor, ML-05, that elicited profound antitumor activity when injected locally, and was associated with the activation of antitumor immunity. In addition, ML-05 could sensitize immunotherapies, which suggests great translational value. |
| WOS关键词 | OXIDATIVE STRESS ; CELL-ACTIVATION ; LUNG-CANCER ; IDENTIFICATION ; GLYCOLYSIS ; EXPRESSION ; INNATE ; OPTIMIZATION ; MACROPHAGES ; RESISTANCE |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| WOS记录号 | WOS:000822888400001 |
| 出版者 | WILEY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309322]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Meng, Tao; Xie, Zuoquan |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China; 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China; 3.Univ Chinese Acad Sci, Beijing, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Div Med Chem, Shanghai, Peoples R China; 5.Yichun Univ, Jiangxi Key Lab Act Ingredients Nat Drugs, Yichun, Peoples R China; 6.Nanjing Univ Chinese Med, Coll Pharm, Nanjing, Peoples R China |
| 推荐引用方式 GB/T 7714 | Du, Mengyan,Yu, Ting,Zhan, Qinjinge,et al. Development of a novel lactate dehydrogenase A inhibitor with potent antitumor activity and immune activation[J]. CANCER SCIENCE,2022,113(9):2974-2985. |
| APA | Du, Mengyan.,Yu, Ting.,Zhan, Qinjinge.,Li, Han.,Zou, Yiping.,...&Xie, Zuoquan.(2022).Development of a novel lactate dehydrogenase A inhibitor with potent antitumor activity and immune activation.CANCER SCIENCE,113(9),2974-2985. |
| MLA | Du, Mengyan,et al."Development of a novel lactate dehydrogenase A inhibitor with potent antitumor activity and immune activation".CANCER SCIENCE 113.9(2022):2974-2985. |
入库方式： OAI收割
来源：上海药物研究所
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