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1. PLoS One. 2012;7(4):e35487. Epub 2012 Apr 18.

Overcoming Multidrug Resistance via Photodestruction of ABCG2-Rich Extracellular
Vesicles Sequestering Photosensitive Chemotherapeutics.

Goler-Baron V, Assaraf YG.

The Fred Wyszkowski Cancer Research Laboratory, Department of Biology,
Technion-Israel Institute of Technology, Haifa, Israel.

Multidrug resistance (MDR) remains a dominant impediment to curative cancer
chemotherapy. Efflux transporters of the ATP-binding cassette (ABC) superfamily
including ABCG2, ABCB1 and ABCC1 mediate MDR to multiple structurally and
functionally distinct antitumor agents. Recently we identified a novel mechanism
of MDR in which ABCG2-rich extracellular vesicles (EVs) form in between attached
neighbor breast cancer cells and highly concentrate various chemotherapeutics in
an ABCG2-dependent manner, thereby sequestering them away from their
intracellular targets. Hence, development of novel strategies to overcome MDR
modalities is a major goal of cancer research. Towards this end, we here
developed a novel approach to selectively target and kill MDR cancer cells. We
show that illumination of EVs that accumulated photosensitive cytotoxic drugs
including imidazoacridinones (IAs) and topotecan resulted in intravesicular
formation of reactive oxygen species (ROS) and severe damage to the EVs membrane
that is shared by EVs-forming cells, thereby leading to tumor cell lysis and the
overcoming of MDR. Furthermore, consistent with the weak base nature of IAs, MDR
cells that are devoid of EVs but contained an increased number of lysosomes,
highly accumulated IAs in lysosomes and upon photosensitization were efficiently
killed via ROS-dependent lysosomal rupture. Combining targeted lysis of
IAs-loaded EVs and lysosomes elicited a synergistic cytotoxic effect resulting in
MDR reversal. In contrast, topotecan, a bona fide transport substrate of ABCG2,
accumulated exclusively in EVs of MDR cells but was neither detected in lysosomes
of normal breast epithelial cells nor in non-MDR breast cancer cells. This
exclusive accumulation in EVs enhanced the selectivity of the cytotoxic effect
exerted by photodynamic therapy to MDR cells without harming normal cells.
Moreover, lysosomal alkalinization with bafilomycin A1 abrogated lysosomal
accumulation of IAs, consequently preventing lysosomal photodestruction of normal
breast epithelial cells. Thus, MDR modalities including ABCG2-dependent drug
sequestration within EVs can be rationally converted to a pharmacologically
lethal Trojan horse to selectively eradicate MDR cancer cells.

PMCID: PMC3329466
PMID: 22530032 [PubMed - in process]