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Imidazoacridinone-dependent lysosomal photodestruction: a pharmacological Trojan horse approach to eradicate multidrug-resistant cancers
Abstract
Multidrug resistance (MDR) remains a primary hindrance to curative cancer therapy. Thus, introduction of novel strategies to overcome MDR is of paramount therapeutic significance. Sequestration of chemotherapeutics in lysosomes is an established mechanism of drug resistance. Here, we show that MDR cells display a marked increase in lysosome number. We further demonstrate that imidazoacridinones (IAs), which are cytotoxic fluorochromes, undergo a dramatic compartmentalization in lysosomes because of their hydrophobic weak base nature. We hence developed a novel photoactivation-based pharmacological Trojan horse approach to target and eradicate MDR cancer cells based on photo-rupture of IA-loaded lysosomes and tumor cell lysis via formation of reactive oxygen species. Illumination of IA-loaded cells resulted in lysosomal photodestruction and restoration of parental cell drug sensitivity. Lysosomal photodestruction of MDR cells overexpressing the key MDR efflux transporters ABCG2, ABCB1 or ABCC1 resulted in 10- to 52-fold lower IC50 values of various IAs, thereby restoring parental cell sensitivity. Finally, in vivo application of this photodynamic therapy strategy after i.v. injection of IAs in human ovarian tumor xenografts in the chorioallantoic membrane model revealed selective destruction of tumors and their associated vasculature. These findings identify lysosomal sequestration of IAs as an Achilles heel of MDR cells that can be harnessed to eradicate MDR tumor cells via lysosomal photodestruction.
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Authors (10)
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Y Adar
- Technion-Israel Institute of Technology Department of Biology
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Michal Stark
- Technion-Israel Institute of Technology Department of Biology
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Eran E. Bram
- Technion-Israel Institute of Technology Department of Biology
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P Nowak-Sliwinska
- Swiss Federal Institute of Technology Institute of Chemical Sciences and Engineering
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H. van den Bergh
- Swiss Federal Institute of Technology Institute of Chemical Sciences and Engineering
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G Szewczyk
- Jagiellonian University Department of Biophysics
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T. Sarna
- Jagiellonian University Department of Biophysics
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Aw Griffoen
- University Medical Center, Amsterdam Department of Medical Oncology
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Yehuda G. Assaraf
- Technion-Israel Institute of Technology Department of Biology
Cite as
Full text
- Publication version
- Accepted or Published Version
- DOI:
- Digital Object Identifier (open in new tab) 10.1038/cddis.2012.30
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Details
- Category:
- Articles
- Type:
- artykuł w czasopiśmie wyróżnionym w JCR
- Published in:
-
Cell Death and Disease
no. 3,
edition 4,
ISSN: 2041-4889 - Language:
- English
- Publication year:
- 2012
- Bibliographic description:
- Adar Y., Stark M., Bram E., Nowak-Sliwinska P., Van Den Bergh H., Szewczyk G., Sarna T., Skladanowski A., Griffoen A., Assaraf Y.: Imidazoacridinone-dependent lysosomal photodestruction: a pharmacological Trojan horse approach to eradicate multidrug-resistant cancers// Cell Death and Disease. -Vol. 3, iss. 4 (2012),
- DOI:
- Digital Object Identifier (open in new tab) 10.1038/cddis.2012.30
- Verified by:
- Gdańsk University of Technology
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