한빛사논문
- 조회371
Minsu Park 1,2,3, Kyoung Sunwoo 4, Yoon-Jae Kim 1,2,3, Miae Won 4, Yunjie Xu 4,5, Jaewon Kim 4, Zhongji Pu 6, Mingle Li 4, Ji Young Kim 1,3, Jae Hong Seo 1,2,3, Jong Seung Kim 4
1Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 02841, Korea.
2Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 02841, Korea.
3Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul 08308, Korea.
4Department of Chemistry, Korea University, Seoul 02841, Korea.
5Institute of Microscale Optoelectronics, Shenzhen University, Shenzhen 518060, P. R. China.
6Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311200, P. R. China.
M.P. and K.S. contributed equally to this work.
Corresponding Authors : Mingle Li, Ji Young Kim, Jae Hong Seo, Jong Seung Kim
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
논문정보
- Research article
- 2023년 03월 (BRIC 등록일 2023-03-17)
- 국내(교신)+국외 연구진
- 의약학 > 종양의학
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