A small-molecule anti-cancer drug for long-acting lysosomal damage.
10.1016/j.apsb.2025.09.005
- Author:
Shulin ZHAO
1
;
Qingjie BAI
1
;
Guimin XUE
2
;
Juan WANG
3
;
Luyao HU
4
;
Xueqian WANG
1
;
Yan LI
1
;
Shuai LU
5
;
Yangang SUN
3
;
Zhiqiang ZHANG
3
;
Yanling MU
1
;
Yanle ZHI
3
;
Qixin CHEN
1
Author Information
1. School of Pharmaceutical Sciences & Institute of Materia Medica, National Key Laboratory of Advanced Drug Delivery System, Key Laboratory for Biotechnology Drugs of National Health Commission, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China.
2. School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China.
3. Engineering Technology Research Center of TCM Health Industry in Henan Province, Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, China.
4. Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
5. School of Science, China Pharmaceutical University, Nanjing 211198, China.
- Publication Type:Journal Article
- Keywords:
Anticancer;
Fluorescence imaging;
LLAD;
Lysosomal;
SLC38A9;
Small-molecule;
Sub-cellular
- From:
Acta Pharmaceutica Sinica B
2025;15(11):5867-5879
- CountryChina
- Language:English
-
Abstract:
Lysosomes represent a promising target for cancer therapy and reducing drug resistance. However, the short treatment time and low efficiency of lysosomal targeting have limited the application in lysosome-targeting anticancer drugs. In this study, we proposed an adhesive-bandage approach and synthesized a new lysosomal targeting drug, namely long-term lysosome-targeting anticancer drug (LLAD). It contains a SLC38A9-targeting covalently bound moiety and an alkaline component both to prolong the inhibition of SLC38A9 in lysosomes and alkalinize lysosomes. Upon short term and low-dose treatment of HeLa cells, at passage 0, with LLAD, it rapidly alkalinized lysosomes and also can be detected in lysosomes even at passage 15. LLAD induced apoptosis in HeLa cells through long-term lysosomal damage, and showed better long-term anticancer effect than cisplatin in vivo. Overall, our study paves the way for developing long-term lysosomal targeting drugs to treat cancer and overcome the drug resistance of cancer cells, and also provides a candidate drug, LLAD, for treating cancer.
