Photodynamic priming modulates cellular ATP levels to overcome P-glycoprotein-mediated drug efflux in chemoresistant triple-negative breast cancer.
ABC transporter
P‐glycoprotein
cellular ATP levels
drug delivery
multidrug resistance
photodynamic priming
Journal
Photochemistry and photobiology
ISSN: 1751-1097
Titre abrégé: Photochem Photobiol
Pays: United States
ID NLM: 0376425
Informations de publication
Date de publication:
02 Jun 2024
02 Jun 2024
Historique:
revised:
13
05
2024
received:
10
01
2024
accepted:
14
05
2024
medline:
2
6
2024
pubmed:
2
6
2024
entrez:
2
6
2024
Statut:
aheadofprint
Résumé
P-glycoprotein (P-gp, ABCB1) is a well-researched ATP-binding cassette (ABC) drug efflux transporter linked to the development of cancer multidrug resistance (MDR). Despite extensive studies, approved therapies to safely inhibit P-gp in clinical settings are lacking, necessitating innovative strategies beyond conventional inhibitors or antibodies to reverse MDR. Photodynamic therapy is a globally approved cancer treatment that uses targeted, harmless red light to activate non-toxic photosensitizers, confining its cytotoxic photochemical effects to disease sites while sparing healthy tissues. This study demonstrates that photodynamic priming (PDP), a sub-cytotoxic photodynamic therapy process, can inhibit P-gp function by modulating cellular respiration and ATP levels in light accessible regions. Using chemoresistant (VBL-MDA-MB-231) and chemosensitive (MDA-MB-231) triple-negative breast cancer cell lines, we showed that PDP decreases mitochondrial membrane potential by 54.4% ± 30.4 and reduces mitochondrial ATP production rates by 94.9% ± 3.46. Flow cytometry studies showed PDP can effectively improve the retention of P-gp substrates (calcein) by up to 228.4% ± 156.3 in chemoresistant VBL-MDA-MB-231 cells, but not in chemosensitive MDA-MB-231 cells. Further analysis revealed that PDP did not alter the cell surface expression level of P-gp in VBL-MDA-MB-231 cells. These findings indicate that PDP can reduce cellular ATP below the levels that is required for the function of P-gp and improve intracellular substrate retention. We propose that PDP in combination with chemotherapy drugs, might improve the efficacy of chemotherapy and overcome cancer MDR.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : National Science Foundation
ID : 2030253
Organisme : NIH HHS
ID : R01CA256710
Pays : United States
Organisme : NIH HHS
ID : R01CA260340
Pays : United States
Organisme : NIH HHS
ID : R21EB028508
Pays : United States
Informations de copyright
© 2024 The Author(s). Photochemistry and Photobiology published by Wiley Periodicals LLC on behalf of American Society for Photobiology.
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