Cited by 137Photodynamic Therapy Research StudiesDrug Transport and Resistance MechanismsNanoplatforms for cancer theranostics

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The Tyrosine Kinase Inhibitor Imatinib Mesylate Enhances the Efficacy of Photodynamic Therapy by Inhibiting ABCG2

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Liu, Weiguo, Baer, Maria R., Bowman, Mary Jo, Pera, Paula, Zheng, Xiang, Morgan, Janet, Pandey, Ravindra A., Oseroff, Allan R.·2007·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-06-1599

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Abstract

Purpose: The ATP-binding cassette protein ABCG2 (breast cancer resistance protein) effluxes some of the photosensitizers used in photodynamic therapy (PDT) and, thus, may confer resistance to this treatment modality. Tyrosine kinase inhibitors (TKI) can block the function of ABCG2. Therefore, we tested the effects of the TKI imatinib mesylate (Gleevec) on photosensitizer accumulation and in vitro and in vivo PDT efficacy. Experimental Design: Energy-dependent photosensitizer efflux and imatinib mesylate's effects on intracellular accumulation of clinically used second- and first-generation photosensitizers were studied by flow cytometry in murine and human cells with and without ABCG2 expression. Effects of ABCG2 inhibition on PDT were examined in vitro using cell viability assays and in vivo measuring photosensitizer accumulation and time to regrowth in a RIF-1 tumor model. Results: Energy-dependent efflux of 2-(1-hexyloxethyl)-2-devinyl pyropheophorbide-a (HPPH, Photochlor), endogenous protoporphyrin IX (PpIX) synthesized from 5-aminolevulenic acid, and the benzoporphyrin derivative monoacid ring A (BPD-MA, Verteporfin) was shown in ABCG2+ cell lines, but the first-generation multimeric photosensitizer porfimer sodium (Photofrin) and a novel derivative of HPPH conjugated to galactose were minimally transported. Imatinib mesylate increased accumulation of HPPH, PpIX, and BPD-MA from 1.3- to 6-fold in ABCG2+ cells, but not in ABCG2− cells, and enhanced PDT efficacy both in vitro and in vivo. Conclusions: Second-generation clinical photosensitizers are transported out of cells by ABCG2, and this effect can be abrogated by coadministration of imatinib mesylate. By increasing intracellular photosensitizer levels in ABCG2+ tumors, imatinib mesylate or other ABCG2 transport inhibitors may enhance efficacy and selectivity of clinical PDT.

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Authors: Liu, W., Baer, M. R., Bowman, M. J., Pera, P., Zheng, X., Morgan, J., Pandey, R. A., & Oseroff, A. R.
Affiliations: 1Dermatology, Departments of
2Medicine, and
Roswell Park Comprehensive Cancer Center (US)
ORCID: Liu, Weiguo
Baer, Maria R.
Zheng, Xiang
Morgan, Janet
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2007-04-15
Volume: 13
Issue: 8
Pages: 2463-2470
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-06-1599
OpenAlex: W2147445587
Cited by: 136
References: 47
Citations by year: 2026: 1 · 2025: 3 · 2024: 7 · 2023: 9 · 2022: 7 · 2021: 4 · 2020: 6 · 2019: 9 · 2018: 7 · 2017: 7 · 2016: 2 · 2015: 12 · 2014: 13 · 2013: 6 · 2012: 12
FWCI: 5.49
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
Funders: National Cheng Kung University Hospital
National Cancer Institute (P30 CA16056, P01 CA55791, P01CA055791, P30CA016056)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Photodynamic Therapy Research Studies
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
Keywords: imatinib mesylate, ABCG2, photodynamic therapy, photosensitizer accumulation, tyrosine kinase inhibitors, drug resistance, HPPH, protoporphyrin IX, verteporfin, porfimer sodium, combination therapy
MeSH terms: Imatinib Mesylate, ATP Binding Cassette Transporter, Subfamily G, Member 2, Antineoplastic Agents, Benzamides, Carcinoma, Squamous Cell, Combined Modality Therapy, Humans, Hypopharyngeal Neoplasms, Neoplasm Proteins, Photochemotherapy, Piperazines, Protein-Tyrosine Kinases, Pyrimidines, Photosensitizing Agents, ATP-Binding Cassette Transporters, Cell Line, Tumor

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The Tyrosine Kinase Inhibitor Imatinib Mesylate Enhances the Efficacy of Photodynamic Therapy by Inhibiting ABCG2

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