Lansoprazole (LPZ) reverses multidrug resistance (MDR) in cancer through impeding ATP-binding cassette (ABC) transporter-mediated chemotherapeutic drug efflux and lysosomal sequestration.

Autor:	Ji N; Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China., Li H; Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China., Zhang Y; Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China., Li Y; Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China., Wang P; Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China., Chen X; Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China., Liu YN; Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China., Wang JQ; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA., Yang Y; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA., Chen ZS; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA., Li Y; Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China. Electronic address: yli08@tmu.edu.cn., Wang R; Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China. Electronic address: wangran@tmu.edu.cn., Kong D; Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin 300060, China; Tianjin Medical University, Tianjin 300070, China; Key Laboratory of Immune Microenvironment and Diseases (Ministry of Education), Tianjin Medical University, Tianjin 300070, China. Electronic address: kongdexin@tmu.edu.cn.
Jazyk:	angličtina
Zdroj:	Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy [Drug Resist Updat] 2024 Sep; Vol. 76, pp. 101100. Date of Electronic Publication: 2024 Jun 04.
DOI:	10.1016/j.drup.2024.101100
Abstrakt:	Aims: Lansoprazole is one of the many proton pump inhibitors (PPIs) that acts more strongly with ABCB1 and ABCG2. The present study is to investigate the potential of lansoprazole on reversal of ABCB1/G2-mediated MDR in cancer, in vitro and in vivo. Methods: Reversal studies and combination evaluation were conducted to determine the synergistic anti-MDR effects on lansoprazole. Lysosomal staining was used to determination of lansoprazole on ABCB1-mediated lysosomal sequestration. Substrate accumulation and efflux assays, ATPase activity, and molecular docking were conducted to evaluate lansoprazole on ABCB1/G2 functions. Western blot and immunofluorescence were used to detect lansoprazole on ABCB1/G2 expression and subcellular localization. MDR nude mice models were established to evaluate the effects of lansoprazole on MDR in vivo. Results: Lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects with substrate drugs in MDR cells. In vivo experiments demonstrated that lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects that augmented the sensitivity of substrate anticancer drugs in ABCB1/G2-mediated settings without obvious toxicity. Lansoprazole impeded lysosomal sequestration mediated by ABCB1, leading to a substantial increase in intracellular accumulation of substrate drugs. The effects of lansoprazole were not attributable to downregulation or alterations in subcellular localization of ABCB1/G2. Lansoprazole promoted the ATPase activity of ABCB1/G2 and competitively bound to the substrate-binding region of ABCB1/G2. Conclusions: These findings present novel therapeutic avenues whereby the combination of lansoprazole and chemotherapeutic agents mitigates MDR mediated by ABCB1/G2 overexpression. Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Zhe-Sheng Chen is the editor-in-chief of Drug Resistance Updates. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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