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.

Imidazoacridinone Derivatives as Efficient Sensitizers in Photoantimicrobial Chemotherapy

“…The results obtained point out that accumulation of C1330 in particular structures is crucial for the effective photokilling of C. albicans cells. In accordance with observations made by others (3,26,29), we observed that the nucleus is not the only structure where C1330 accumulates (30 min at 100 M) (Fig. 6A).…”

“…Imidazoacridinones accumulate effectively in lysosomes of tumor cells, due to their weak base nature. Alkalization of the cells with bafilomycin or ammonium chloride abolished selective accumulation of IA in cell lysosomes and promoted accumulation in the nucleus (26). Under our experimental conditions, we observed that in C. albicans cells, C1330 accumulated efficiently in the nucleus.…”

“…Dark toxicity toward human cells in our experimental model was not observed, in contrast to previously published results, where some dark toxicity was noticed. Cells incubated with C1330 at a concentration of 10 M, upon illumination, decreased their survival to 30% and 50% of the controls (nonilluminated cells) for the human cancer cell line A549 and its multidrug resistance phenotype counterpart, A549/K1.5 (26). Under our experimental conditions, the studied HaCaT cell line survived the dark treatment, even at a C1330 concentration of 50 M (Fig.…”

“…Here, we present data concerning a novel representative of a group of photosensitizing agents that so far have been studied as anticancer drugs exhibiting their mechanism of action through DNA binding and trapping the DNA-topoisomerase II-cleavable complexes. It was only recently found that the compounds from the imidazoacridinone group, exemplified by C1330, are also able to act through the light-dependent lysosome-destructive pathway, thus overcoming the MDR (multidrug resistance) phenotype in several cancer cell lines (26). This light-dependent action encouraged us to study the potential fungicidal action of imidazoacridinone agents against C. albicans in a light-dependent way.…”

The Great Escape; the Hallmarks of Resistance to Antiangiogenic Therapy

“…Vesicles that reside intracellularly have also been implicated in resistance to antiangiogenic therapy. This relates to the sequestration and accumulation of therapeutic compounds in the lysosomes and endocytic vesicles, a phenomenon that has already been described for chemotherapeutics Adar et al, 2012) and photosensitizing compounds . We recently showed that this also applies to one of the antiangiogenic TKIs, i.e., sunitinib.…”