Journal
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
Volume 4, Issue 5, Pages 1578-1587Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsptsci.1c00138
Keywords
photodynamic therapy; cancer drug resistance; ABCB1; ABCG2; ATPase activity; protein cross-linking
Categories
Funding
- National Institutes of Health (NIH) [R01CA260340, R21EB028508]
- National Science Foundation [CBET-2030253]
- UMD-NCI Partnership for Integrative Cancer Research seed grant
- Intramural Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research
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Efforts to overcome cancer multidrug resistance through inhibition of ABC drug transporters have largely failed, prompting a need for new strategies. This study demonstrates how photodynamic therapy can manipulate the function and integrity of ABC drug transporters to overcome resistance, providing insights for the development of new optical tools.
Efforts to overcome cancer multidrug resistance through inhibition of the adenosine triphosphate-binding cassette (ABC) drug transporters ABCB1 and ABCG2 have largely failed in the clinic. The challenges faced during the development of nontoxic modulators suggest a need for a conceptual shift to new strategies for the inhibition of ABC drug transporters. Here, we reveal the fundamental mechanisms by which photodynamic therapy (PDT) can be exploited to manipulate the function and integrity of ABC drug transporters. PDT is a clinically relevant, photochemistry-based tool that involves the light activation of photosensitizers to generate reactive oxygen species. ATPase activity and in silico molecular docking analyses show that the photosensitizer benzoporphyrin derivative (BPD) binds to ABCB1 and ABCG2 with micromolar half-maximal inhibitory concentrations in the absence of light. Light activation of BPD generates singlet oxygen to further reduce the ATPase activity of ABCB1 and ABCG2 by up to 12-fold in an optical dose-dependent manner. Gel electrophoresis and Western blotting revealed that light-activated BPD induces the aggregation of these transporters by covalent cross-linking. We provide a proof of principle that PDT affects the function of ABCB1 and ABCG2 by modulating the ATPase activity and protein integrity of these transporters. Insights gained from this study concerning the photodynamic manipulation of ABC drug transporters could aid in the development and application of new optical tools to overcome the multidrug resistance that often develops after cancer chemotherapy.
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