Citation: Daili Liu, Changxiang Yu, Liyuan Lin, Zhidong Liu, Guiqian Fang, Qingqiang Yao, Qixin Chen, Xintian Shao. Berberrubine-mediated pH indicator response enhances the efficacy of hydroxycamptothecin by reversing lysosomal drug resistance[J]. Chinese Chemical Letters, ;2025, 36(9): 110718. doi: 10.1016/j.cclet.2024.110718 shu

Berberrubine-mediated pH indicator response enhances the efficacy of hydroxycamptothecin by reversing lysosomal drug resistance

Daili Liu ^{a, b, 1} ,
Changxiang Yu ^{a, 1} ,
Liyuan Lin ^{b, c} ,
Zhidong Liu ^{a, d, *,} ,
Guiqian Fang ^{c, *,} ,
Qingqiang Yao ^c ,
Qixin Chen ^{c, e, *,} ,
Xintian Shao ^{b, *,}

a.
School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
b.
School of Life Sciences, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan 250117, China
c.
School of Pharmaceutical Sciences & Institute of Materia Medica, Medical Science and Technology Innovation Center, State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan 250117, China
d.
State Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
e.
Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore 119074, Singapore

liuzhidong@tjutcm.edu.cn

gqfang@email.sdfmu.edu.cn

chenqixin@sdfmu.edu.cn

shaoxintian@sdfmu.edu.cn

Received Date: 29 September 2024
Revised Date: 25 November 2024
Accepted Date: 3 December 2024
Available Online: 9 December 2024

Figures(5)

Drug resistance poses a significant challenge to effective long-term treatment across various medical fields. This study proposed a feasible strategy to enhance lysosomal alkalinization by transporting mitochondria-targeting quaternary ammonium salts into lysosomes, creating a deprotonated environment. This environment allows drugs to bypass protonation issues in lysosomes, thereby reversing drug resistance and improving therapeutic efficacy. As a proof of concept, a quaternary ammonium salt-based pH indicator was developed, berberrubine (BRB), enhancing the action of the anticancer drug hydroxycamptothecin (HCPT) in resistant cells. BRB-induced alkalinization increased lysosomal pH and deactivated lysosomal activity, enabling HCPT to bypass protonation constraints. This enhancement markedly improved the anticancer efficacy of HCPT in resistant cells, providing an innovative approach to address drug resistance and advancing therapeutic technologies.
- Drug resistance,
- Lysosomes,
- Berberrubine,
- Hydroxycamptothecin,
- Quaternary ammonium salts,
- Alkalinization
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