A New Strategy to Fight Metallodrug Resistance: Mitochondria‐Relevant Treatment through Mitophagy to Inhibit Metabolic Adaptations of Cancer Cells

• Published in: Angewandte Chemie International Edition Vol. 61; no. 27; pp. e202203843 - n/a
• Main Authors: Wang, Meng‐Meng, Xu, Fu‐Jie, Su, Yan, Geng, Yun, Qian, Xiao‐Ting, Xue, Xu‐Ling, Kong, Ya‐Qiong, Yu, Zheng‐Hong, Liu, Hong‐Ke, Su, Zhi
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 04-07-2022
• Edition: International ed. in English
• Subjects: Adaptation; ATP; Autophagy; Bioenergetics; Cancer; Cisplatin; Glycolysis; Iridium; Metabolic Adaptation; Metallodrug Resistance; Mitochondria; Mitochondria-Targeting; Mitophagy; Platinum; Spheroids; Transcriptomes; Tumors; mitophagy, metabolic adaptation, mitochondria-targeting, metallodrug resistance
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202203843

Metabolic adaptations can help cancer cells to escape from chemotherapeutics, mainly involving autophagy and ATP production. Herein, we report a new rhein‐based cyclometalated IrIII complex, Ir‐Rhein, that can accurately target mitochondria and effectively inhibit metabolic adaptations. The complex Ir‐Rhein induces severe mitochondrial damage and initiates mitophagy to reduce the number of mitochondria and subsequently inhibit both mitochondrial and glycolytic bioenergetics, which eventually leads to ATP starvation death. Moreover, Ir‐Rhein can overcome cisplatin resistance. Co‐incubation experiment, 3D tumor spheroids experiment and transcriptome analysis reveal that Ir‐Rhein shows promising antiproliferation performance for cisplatin‐resistant cancer cells with the regulation of platinum resistance‐related transporters. To our knowledge, this is a new strategy to overcome metallodrug resistance with a mitochondria‐relevant treatment.
A new strategy to fight metallodrug resistance through mitochondria‐relevant treatment is reported. The cyclometalated IrIII complex Ir‐Rhein could inhibit the metabolic adaptation of cancer cells by inducing severe mitochondrial damage and dysfunction. Moreover, complex Ir‐Rhein could overcome metallodrug resistance through the regulation of the platinum resistance‐related transporters.