A New Strategy to Fight Metallodrug Resistance: Mitochondria‐Relevant Treatment through Mitophagy to Inhibit Metabolic Adaptations of Cancer Cells. (5th May 2022)

• Record Type: Journal Article
• 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
• Is Part Of: Angewandte Chemie. Volume 134:Number 27(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-05-05
• Subjects: Iridium -- Metabolic Adaptation -- Metallodrug Resistance -- Mitochondria-Targeting -- Mitophagy; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202203843
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: Metabolic adaptations can help cancer cells to escape from chemotherapeutics, mainly involving autophagy and ATP production. Herein, we report a new rhein‐based cyclometalated Ir III 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. Abstract : A new strategy to fight metallodrug resistance through mitochondria‐relevant treatment is reported. The cyclometalated Ir III 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.