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
1. [1]
  N. Vasan, J. Baselga, D.M. Hyman, Nature 575 (2019) 299–309. doi: 10.1038/s41586-019-1730-1
2. [2]
  L. Zhao, X. Guo, Z. Zhang, et al., Chin. Chem. Lett. 35 (2024) 109506. doi: 10.1016/j.cclet.2024.109506
3. [3]
  K. Zhang, H. Ying, R. Zhao, Y. Chen, Q. Deng, Chin. Herb. Med. 14 (2022) 111–116.
4. [4]
  K. Sunwoo, M. Won, K.P. Ko, et al., Chem 6 (2020) 1408–1419. doi: 10.1016/j.chempr.2020.03.004
5. [5]
  R. Nussinov, C.J. Tsai, H. Jang, Drug Resist. Updat. 59 (2021) 100796. doi: 10.1016/j.drup.2021.100796
6. [6]
  J. Zhai, Z. Song, H. Chang, et al., Chin. Herb. Med. 14 (2022) 79–89.
7. [7]
  Y. Tian, B. Ma, S. Yu, et al., Chin. Herb. Med. 15 (2023) 169–180.
8. [8]
  J. Guo, M.F. Wang, Y. Zhu, et al., Acta Mater. Med. 2 (2023) 172–190.
9. [9]
  N.A. Hussein, S. Malla, M.A. Pasternak, et al., Drug Resist. Update. 57 (2021) 100769. doi: 10.1016/j.drup.2021.100769
10. [10]
  B. Zhitomirsky, Y.G. Assaraf, Drug Resist. Update. 24 (2016) 23–33. doi: 10.1016/j.drup.2015.11.004
11. [11]
  J.F. Pizzolato, L.B. Saltz, Lancet 361 (2003) 2235–2242. doi: 10.1016/S0140-6736(03)13780-4
12. [12]
  L. Jing, S. Shao, Y. Wang, et al., Theranostics 6 (2016) 40–53. doi: 10.7150/thno.13250
13. [13]
  G. Li, Q. Jin, F. Xia, et al., Acta Mater. Med. 2 (2023) 54–63.
14. [14]
  M. Chen, Y. Qiao, J. Cao, et al., J. Nanobiotechnol. 20 (2022) 273. doi: 10.1186/s12951-022-01491-w
15. [15]
  J.R. Lakkakula, P. Gujarathi, P. Pansare, et al., Carbohyd. Polym. 259 (2021) 117696. doi: 10.1016/j.carbpol.2021.117696
16. [16]
  X. Meng, Y. Zhao, B. Han, et al., Nat. Commun. 11 (2020) 594. doi: 10.1038/s41467-019-14036-x
17. [17]
  M.S. Tomar, A. Kumar, C. Srivastava, A. Shrivastava, Biochim. Biophys. Acta Rev. Cancer 1876 (2021) 188616. doi: 10.1016/j.bbcan.2021.188616
18. [18]
  X.N. Zhang, K.D. Yang, C. Chen, et al., Cell Res. 31 (2021) 1072–1087. doi: 10.1038/s41422-021-00528-3
19. [19]
  O. Al-Sawaf, C. Zhang, M. Tandon, et al., Lancet Oncol. 21 (2020) 1188–1200. doi: 10.1016/S1470-2045(20)30443-5
20. [20]
  J.P. Sharman, M. Egyed, W. Jurczak, et al., Lancet 395 (2020) 1278–1291. doi: 10.1016/S0140-6736(20)30262-2
21. [21]
  A. Agudo-López, E. Prieto-García, J. Alemán, et al., Mol. Cancer 16 (2017) 45. doi: 10.1186/s12943-017-0618-7
22. [22]
  Z.M. Huang, M. Chinen, P.J. Chang, et al., Proc. Natl. Acad. Sci. U. S. A. 109 (2011) 553–558.
23. [23]
  N. Ashwanikumar, N.A. Kumar, S.Asha Nair, et al., Acta Biomater. 10 (2014) 4685–4694. doi: 10.1016/j.actbio.2014.07.032
24. [24]
  L. Metterle, C. Nelson, N. Patel, J. Am. Acad. Dermatol. 74 (2016) 552–557. doi: 10.1016/j.jaad.2015.09.040
25. [25]
  M. Sabitha, N. Sanoj Rejinold, A. Nair, et al., Carbohyd. Polym. 91 (2013) 48–57. doi: 10.1016/j.carbpol.2012.07.060
26. [26]
  D. Sun, W. Gao, H. Hu, S. Zhou, Acta Pharm. Sin. B 12 (2022) 3049–3062. doi: 10.1016/j.apsb.2022.02.002
27. [27]
  D.G. Brown, H.J. Wobst, A. Kapoor, L.A. Kenna, N. Southall, Nat. Rev. Drug. Discov. 21 (2022) 793–794. doi: 10.1038/d41573-021-00190-9
28. [28]
  G. Zhu, Y. Zhao, W. Zhang, et al., Chin. Chem. Lett. 35 (2024) 108466. doi: 10.1016/j.cclet.2023.108466
29. [29]
  Y. Zhu, P. Li, C. Liu, et al., Chin. Chem. Lett. 34 (2023) 107543. doi: 10.1016/j.cclet.2022.05.057
30. [30]
  J. Wang, L. Qiu, Theranostics 12 (2022) 3977–3994. doi: 10.7150/thno.70852
31. [31]
  Y. Zeng, X. Zhang, D. Lin, J. Hematol. Oncol. 14 (2021) 189. doi: 10.1186/s13045-021-01199-8
32. [32]
  E. Schrezenmeier, T. Dörner, Nat. Rev. Rheumatol. 16 (2020) 155–166. doi: 10.1038/s41584-020-0372-x
33. [33]
  X. Yi, H. Ji, C. Wang, et al., Appl. Catal. B: Environ. 293 (2021) 120229. doi: 10.1016/j.apcatb.2021.120229
34. [34]
  Y. Xu, Y. Liu, H. Zhou, et al., Talanta 251 (2023) 123738. doi: 10.1016/j.talanta.2022.123738
35. [35]
  Z. Chen, Q. Ye, L. Liu, H. Dong, J. Chromatogr. Sci. 54 (2016) 88–95.
36. [36]
  X.X. Fan, M.Z. Xu, E.L. Leung, Nano-Micro Lett. 12 (2020) 76. doi: 10.1007/s40820-020-0410-x
37. [37]
  X. Shi, T. Zhang, H. Lou, et al., J. Med. Chem. 63 (2020) 11786–11800. doi: 10.1021/acs.jmedchem.0c00881
38. [38]
  W. Chen, X. Ma, H. Chen, S.H. Liu, J. Yin, Coordin. Chem. Rev. 427 (2021) 213584. doi: 10.1016/j.ccr.2020.213584
39. [39]
  A. Delgado-Camón, C. Jarne, V.L. Cebolla, et al., Tetrahedron 71 (2015) 6148–6154. doi: 10.1016/j.tet.2015.06.098
40. [40]
  M.T. Meenu, A.R. Cherian, D.R. Sherin, et al., Dyes Pigm. 194 (2021) 109636. doi: 10.1016/j.dyepig.2021.109636
41. [41]
  Z. Yang, L. Li, J. Ling, et al., Chem. Sci. 11 (2020) 8506–8516. doi: 10.1039/D0SC02837A
42. [42]
  H. Fang, S. Yao, Q. Chen, et al., ACS Nano 13 (2019) 14426–14436. doi: 10.1021/acsnano.9b08011
43. [43]
  H. Zhang, L. Shi, K. Li, et al., Angew. Chem. Int. Ed. 61 (2022) e202116439.
44. [44]
  J. Zhou, S.H. Tan, V. Nicolas, et al., Cell Res. 23 (2013) 508–523. doi: 10.1038/cr.2013.11
45. [45]
  K. Amunugama, G.R. Kolar, D.A. Ford, Front. Immunol. 12 (2021) 701227. doi: 10.3389/fimmu.2021.701227
46. [46]
  X. Wang, S. Zhao, G. Fang, et al., Nanoscale 16 (2024) 8597–8606. doi: 10.1039/D4NR00451E
47. [47]
  J. Zeng, J. Yu, J. Huang, P.R. Chang, J. Disper. Sci. Technol. 33 (2012) 293–306. doi: 10.1080/01932691.2011.562407
48. [48]
  T.C. Chou, Pharmacol. Rev. 58 (2006) 621–681. doi: 10.1124/pr.58.3.10
1. [1]
  Xiaofang Luo , Ye Wu , Xiaokun Zhang , Min Tang , Feiye Ju , Zuodong Qin , Gregory J Duns , Wei-Dong Zhang , Jiang-Jiang Qin , Xin Luan . Peptide-based strategies for overcoming multidrug-resistance in cancer therapy. Chinese Chemical Letters, 2025, 36(1): 109724-. doi: 10.1016/j.cclet.2024.109724
2. [2]
  Shaoqing Du , Xinyong Liu , Xueping Hu , Peng Zhan . Targeting novel sites represents an effective strategy for combating drug resistance. Chinese Chemical Letters, 2025, 36(1): 110378-. doi: 10.1016/j.cclet.2024.110378
3. [3]
  Liping Zhao , Xixi Guo , Zhimeng Zhang , Xi Lu , Qingxuan Zeng , Tianyun Fan , Xintong Zhang , Fenbei Chen , Mengyi Xu , Min Yuan , Zhenjun Li , Jiandong Jiang , Jing Pang , Xuefu You , Yanxiang Wang , Danqing Song . Novel berberine derivatives as adjuvants in the battle against Acinetobacter baumannii: A promising strategy for combating multi-drug resistance. Chinese Chemical Letters, 2024, 35(10): 109506-. doi: 10.1016/j.cclet.2024.109506
4. [4]
  Ruilong Geng , Lingzi Peng , Chang Guo . Dynamic kinetic stereodivergent transformations of propargylic ammonium salts via dual nickel and copper catalysis. Chinese Chemical Letters, 2024, 35(8): 109433-. doi: 10.1016/j.cclet.2023.109433
5. [5]
  Yong-Dan Zhao , Yidan Wang , Rongrong Wang , Lina Chen , Hengtong Zuo , Xi Wang , Jihong Qiang , Geng Wang , Qingxia Li , Canqi Ping , Shuqiu Zhang , Hao Wang . Reversing artemisinin resistance by leveraging thermo-responsive nanoplatform to downregulating GSH. Chinese Chemical Letters, 2024, 35(6): 108929-. doi: 10.1016/j.cclet.2023.108929
6. [6]
  Yixuan Wang , Jiexin Li , Zhihao Shang , Chengcheng Feng , Jianmin Gu , Maosheng Ye , Ran Zhao , Danna Liu , Jingxin Meng , Shutao Wang . Wettability-driven synergistic resistance of scale and oil on robust superamphiphobic coating. Chinese Chemical Letters, 2024, 35(7): 109623-. doi: 10.1016/j.cclet.2024.109623
7. [7]
  Yuxin Li , Chengbin Liu , Qiuju Li , Shun Mao . Fluorescence analysis of antibiotics and antibiotic-resistance genes in the environment: A mini review. Chinese Chemical Letters, 2024, 35(10): 109541-. doi: 10.1016/j.cclet.2024.109541
8. [8]
  Linghui Zou , Meng Cheng , Kaili Hu , Jianfang Feng , Liangxing Tu . Vesicular drug delivery systems for oral absorption enhancement. Chinese Chemical Letters, 2024, 35(7): 109129-. doi: 10.1016/j.cclet.2023.109129
9. [9]
  Fengjie Liu , Fansu Meng , Zhenjiang Yang , Huan Wang , Yuehong Ren , Yu Cai , Xingwang Zhang . Exosome-biomimetic nanocarriers for oral drug delivery. Chinese Chemical Letters, 2024, 35(9): 109335-. doi: 10.1016/j.cclet.2023.109335
10. [10]
  Jinjie Lu , Qikai Liu , Yuting Zhang , Yi Zhou , Yanbo Zhou . Antibacterial performance of cationic quaternary phosphonium-modified chitosan polymer in water. Chinese Chemical Letters, 2024, 35(9): 109406-. doi: 10.1016/j.cclet.2023.109406
11. [11]
  Haiyang Peng , Zhipeng Xie , Shuiqing Lu , Da Zhang , Bin Yang , Feng Liang . Dual-functionality composites of polyaniline-coated oxidized carbon nanohorns: Efficient wave absorption and enhanced corrosion resistance. Chinese Chemical Letters, 2025, 36(6): 110818-. doi: 10.1016/j.cclet.2025.110818
12. [12]
  Chunshi He , Linqing Li , Yuanrong Sun , Xuefang Wang , Jie Ren , Jianbo Li . Enhanced durability of a novel thiol-epoxy network thermosets with excellent hygrothermal and chemical resistance. Chinese Chemical Letters, 2025, 36(6): 110905-. doi: 10.1016/j.cclet.2025.110905
13. [13]
  Hao Li , Hanzhi Lu , Linlin Hu , Xueli Zhang , Hua Shao , Fulun Li , Yanfei Shen . Dynamic surface-enhanced Raman spectroscopy-based metabolic profiling: A novel pathway to overcoming antifungal resistance. Chinese Chemical Letters, 2025, 36(7): 110342-. doi: 10.1016/j.cclet.2024.110342
14. [14]
  Yujie Li , Ya-Nan Wang , Yin-Gen Luo , Hongcai Yang , Jinrui Ren , Xiao Li . Advances in synthetic biology-based drug delivery systems for disease treatment. Chinese Chemical Letters, 2024, 35(11): 109576-. doi: 10.1016/j.cclet.2024.109576
15. [15]
  Qijie Gong , Jian Song , Yihui Song , Kai Tang , Panpan Yang , Xiao Wang , Min Zhao , Liang Ouyang , Li Rao , Bin Yu , Peng Zhan , Saiyang Zhang , Xiaojin Zhang . New techniques and strategies in drug discovery (2020–2024 update). Chinese Chemical Letters, 2025, 36(3): 110456-. doi: 10.1016/j.cclet.2024.110456
16. [16]
  Shifang Song , Chenyu Wu , Li Zhang , Dezhi Yang , Yang Lu , Zhengzheng Zhou . Unpacking phase transitions in multi-component drug systems: A case study. Chinese Chemical Letters, 2025, 36(7): 110911-. doi: 10.1016/j.cclet.2025.110911
17. [17]
  Quanxing Mao , Zhengliang Wang , Zhinan Hu , Ziqi Yang , Hui Li , Yali Yao , Zijun Yong , Tianyi Ma . Facial detection of formaldehyde by using acidichromic carbon dots and the reaction between formaldehyde and ammonium chloride. Chinese Chemical Letters, 2025, 36(7): 110499-. doi: 10.1016/j.cclet.2024.110499
18. [18]
  Xiang Huang , Dongzhen Xu , Yang Liu , Xia Huang , Yangfan Wu , Dongmei Fang , Bing Xia , Wei Jiao , Jian Liao , Min Wang . Asymmetric synthesis of difluorinated α-quaternary amino acids (DFAAs) via Cu-catalyzed difluorobenzylation of aldimine esters. Chinese Chemical Letters, 2024, 35(12): 109665-. doi: 10.1016/j.cclet.2024.109665
19. [19]
  Ya-Ling Li , Jia-Wei Ke , Yue Liu , Dong-Mei Yao , Jing-Dong Zhang , You-Cai Xiao , Fen-Er Chen . Asymmetric conjugated addition of aryl Grignard reagents for the construction of chromanones bearing quaternary stereogenic centers in batch and flow. Chinese Chemical Letters, 2025, 36(6): 110377-. doi: 10.1016/j.cclet.2024.110377
20. [20]
  Xiaojun Wang , Yizhou Zhang , Linwei Guo , Jianwei Li , Peng Wang , Lei Yang , Zhiming Liu . V₂CT_X MXene-derived ammonium vanadate with robust carbon skeleton for superior rate aqueous zinc-ion batteries. Chinese Chemical Letters, 2025, 36(8): 111231-. doi: 10.1016/j.cclet.2025.111231

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(9)
HTML views(1)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142