A Cyclometalated Iridium(III) Complex Exerts High Anticancer Efficacy via Fatty Acid Beta-Oxidation Inhibition and Sphingolipid Metabolism Reprogramming,Journal of Medicinal Chemistry

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A Cyclometalated Iridium(III) Complex Exerts High Anticancer Efficacy via Fatty Acid Beta-Oxidation Inhibition and Sphingolipid Metabolism Reprogramming
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-03 , DOI: 10.1021/acs.jmedchem.4c00280
Cuiyan Lin _{1,

2} , Huiling Wang _{1,

2} , Keyu Chen ₂ , Shuangqiang Liu ₂ , Zhichen Mao ₂ , Zuyu Mo _{2,

3} , Rizhen Huang ₂ , Ye Zhang ₂ , Wei Xie ₄ , Jianhua Wei _{1,

2,

3,

4} , Junfei Jin _{1,

4,

5,

6,

7}

Affiliation

Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China.
Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, Key Laboratory of Medical Biotechnology and Translational Medicine, School of Pharmacy, Guilin Medical University, Guilin, Guangxi 541199, China.
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Centre for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University, Nanjing 210096, China.
Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China.
China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin, Guangxi 541001, China.
Laboratory of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China.

Given the extensive role of lipids in cancer development, there is substantial clinical interest in developing therapies that target lipid metabolism. In this study, we identified one cyclometalated iridium complex (Ir2) that exhibits potent antiproliferation activity in MIA PaCa-2 cells by regulating fatty acid metabolism and sphingolipid metabolism simultaneously. Ir2 also efficiently overcomes cisplatin resistance in vitro. Satisfyingly, the generated Ir2@F127 carriers, as a temperature-sensitive in situ gelling system of Ir2, showed effective cancer treatment with minimal side effects in an in vivo xenograft study. To the best of our knowledge, Ir2 is the first reported cyclometalated iridium complex that exerts anticancer activity in MIA PaCa-2 cells by intervening in lipid metabolism, which provides an alternative pathway for the anticancer mechanism of cyclometalated iridium complexes.

中文翻译：

环金属化铱 (III) 复合物通过脂肪酸 β 氧化抑制和鞘脂代谢重编程发挥高抗癌功效

鉴于脂质在癌症发展中的广泛作用，临床对开发针对脂质代谢的疗法具有很大的兴趣。在这项研究中，我们鉴定了一种环金属化铱络合物 ( Ir2 )，它通过同时调节脂肪酸代谢和鞘脂代谢，在 MIA PaCa-2 细胞中表现出有效的抗增殖活性。 Ir2还能有效克服体外顺铂耐药性。令人满意的是，所生成的 Ir2@F127 载体作为Ir2的温度敏感原位胶凝系统，在体内异种移植研究中显示出有效的癌症治疗效果，且副作用最小。据我们所知， Ir2是第一个报道的环金属铱配合物，通过干预脂质代谢在MIA PaCa-2细胞中发挥抗癌活性，这为环金属铱配合物的抗癌机制提供了一条替代途径。

更新日期：2024-09-03

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