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.
Highlights
The frequent emergence of multidrug resistance (MDR) to structurally and functionally unrelated anticancer drugs, is a major impediment to curative cancer chemotherapy.[4,5,6,7,8,9]
Our current findings show that the achievement of an IAsdependent lysosomal photodestruction in tumor cells relies on the striking sequestration of IAs in lysosomes
Several lines of evidence support the differential compartmentalization of IAs within lysosomes of tumor cells: (i) parental A549 and their ABCG2-overexpressing MDR subline displayed co-localization of C-1330 and the established lysosomal marker, LysoTracker red; (ii) alkalinization of the acidic lysosomal pH either with bafilomycin A1, a potent inhibitor of lysosomal H þ -ATPase, or ammonium chloride, an established weak base lysosomotropic alkalinization agent, resulted in the complete abrogation of lysosomal C-1330 accumulation
Summary
On the basis of these results and based on the markedly increased number of lysosomes per ABCG2overexpressing MDR A549/K1.5 cell, we further explored the hypothesis that MDR cells may become highly sensitive to the cytotoxic effect elicited by IAs upon lysosomal photodestruction, resulting in the overcoming of MDR. To this end, we first determined the cytotoxic activity of C-1330 in A549 and A549/K1.5 cells (Figures 3c and d, respectively) in the presence or absence of photosensitization. This was accompanied by massive destruction of the ovarian tumor xenografts
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