Cutting Off H plus Leaks on the Inner Mitochondrial Membrane: A Proton Modulation Approach to Selectively Eradicate Cancer Stem Cells
- Authors
- Park, Minsu; Sunwoo, Kyoung; Kim, Yoon-Jae; Won, Miae; Xu, Yunjie; Kim, Jaewon; Pu, Zhongji; Li, Mingle; Kim, Ji Young; Seo, Jae Hong; Kim, Jong Seung
- Issue Date
- Mar-2023
- Publisher
- American Chemical Society
- Citation
- Journal of the American Chemical Society, v.145, no.8, pp 4647 - 4658
- Pages
- 12
- Indexed
- SCIE
SCOPUS
- Journal Title
- Journal of the American Chemical Society
- Volume
- 145
- Number
- 8
- Start Page
- 4647
- End Page
- 4658
- URI
- https://scholarworks.korea.ac.kr/kumedicine/handle/2021.sw.kumedicine/62461
- DOI
- 10.1021/jacs.2c12587
- ISSN
- 0002-7863
1520-5126
- Abstract
- Cancer stem cells (CSCs) are associated with the invasion and metastatic relapse of various cancers. However, current cancer therapies are limited to targeting the bulk of primary tumor cells while remaining the CSCs untouched. Here, we report a new proton (H+) modulation approach to selectively eradicate CSCs via cutting off the H+ leaks on the inner mitochondrial membrane (IMM). Based on the fruit extract of Gardenia jasminoides, a multimodal molecule channel blocker with high biosafety, namely, Bo-Mt-Ge, is developed. Importantly, in this study, we successfully identify that mitochondrial uncoupling protein UCP2 is closely correlated with the stemness of CSCs, which may offer a new perspective for selective CSC drug discovery. Mechanistic studies show that Bo-Mt-Ge can specifically inhibit the UCP2 activities, decrease the H+ influx in the matrix, regulate the electrochemical gradient, and deplete the endogenous GSH, which synergistically constitute a unique MoA to active apoptotic CSC death. Intriguingly, Bo-Mt-Ge also counteracts the therapeutic resistance via a two-pronged tactic: drug efflux pump P-glycoprotein downregulation and antiapoptotic factor (e.g., Bcl-2) inhibition. With these merits, Bo-Mt-Ge proved to be one of the safest and most efficacious anti-CSC agents, with ca. 100-fold more potent than genipin alone in vitro and in vivo. This study offers new insights and promising solutions for future CSC therapies in the clinic.
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- Appears in
Collections - 2. Clinical Science > Department of Medical Oncology and Hematology > 1. Journal Articles
- 4. Research institute > Cancer Institute > 1. Journal Articles
- 3. Graduate School > Graduate School > 1. Journal Articles
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