Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein
Abstract
BACKGROUND: Multidrug resistance (MDR) is a significant obstacle to providing effective chemotherapy to many patients. Multifactorial in etiology, classic MDR is associated with the overexpression of P-glycoprotein (P-gp), resulting in increased efflux of chemotherapy from cancer cells. Inhibiting P-gp as a method to reverse MDR in cancer patients has been studied extensively, but the results have generally been disappointing. METHODS: The development of P-gp inhibitors is reviewed, including a discussion of early agents that are no longer being developed and third-generation agents that are currently in clinical trials. RESULTS: First-generation agents (eg, cyclosporin, verapamil) were limited by unacceptable toxicity, whereas second-generation agents (eg, valspodar, biricodar) had better tolerability but were confounded by unpredictable pharmacokinetic interactions and interactions with other transporter proteins. Third-generation inhibitors (tariquidar XR9576, zosuquidar LY335979, laniquidar R101933, and ONT-093) have high potency and specificity for P-gp. Furthermore, pharmacokinetic studies to date have shown no appreciable impact on cytochrome P450 3A4 drug metabolism and no clinically significant drug interactions with common chemotherapy agents. CONCLUSIONS: Third-generation P-gp inhibitors have shown promise in clinical trials. The continued development of these agents may establish the true therapeutic potential of P-gp-mediated MDR reversal.
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Overexpression of drug resistance-associated genes, such as P-gp and Bcl-2, is one of the most consistent alterations in multidrug resistant cells.
“Overexpression of drug resistance-associated genes, such as P-gp and Bcl-2, is one of the most consistent alterations in multidrug resistant cells [131–134].”
From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [132]
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- Authors
- Thomas, H., & Coley, H. M.
- Affiliations
- University of Surrey (GB)
- Venue
- Cancer Control
- Publisher
- SAGE Publications
- Published
- 2003-03
- Volume
- 10
- Issue
- 2
- Pages
- 159-165
- ISSN
- 1073-2748 (ISSN-L)
- OpenAlex
- W84182309
- Cited by
- 931
- References
- 51
- Citations by year
- 2026: 9 · 2025: 20 · 2024: 22 · 2023: 37 · 2022: 19 · 2021: 37 · 2020: 47 · 2019: 51 · 2018: 50 · 2017: 45 · 2016: 57 · 2015: 47 · 2014: 64 · 2013: 44 · 2012: 44
- FWCI
- 20.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Control (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- multidrug resistance, P-glycoprotein, P-glycoprotein inhibitors, multidrug resistance reversal, tariquidar, zosuquidar, valspodar, cyclosporine, verapamil, drug interactions, CYP3A4, clinical trials
- MeSH terms
- Antineoplastic Agents, Humans, Neoplasms, Drug Resistance, Multiple, Drug Resistance, Neoplasm, ATP Binding Cassette Transporter, Subfamily B, Member 1
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