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    Breast cancer resistance protein 121207-31-6 the enemy of hypericin accumulation and T toxicity of hypericin-mediated photodynamic therapy
    Rastislav Jendželovský , Zuzana Jendželovská, Barbora Kuchárová, Peter Fedoročko
    Institute of Biology and Ecology, Department of Cellular Biology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Šrobárova 2, 041 54 Košice, Slovakia
    Photodynamic therapy
    ABC transporters
    Breast cancer resistance protein Promyelocytic leukemia 
    Breast cancer resistance protein (BCRP) belongs to the family of ATP-binding cassette (ABC) transporters, overexpression of which can confer a multidrug-resistant phenotype in cancer cells and tumors. BCRP mediates efflux of numerous xenobiotics, including various chemotherapeutic agents and photosensitizers. Hypericin (HY) is a naturally-occurring photosensitizer synthesized by plants of the genus Hypericum. Our recently published results indicate that accumulation of HY in cancer cells of different tissue origin can be affected mostly by BCRP. Considering all known facts, the main goal of this study was to verify whether not only HY accumulation but also toxicity of HY-mediated photodynamic therapy (PDT) can be affected by the presence of some ABC transporters. To specifically prove our hypothesis, we used an experimental model of human leukemia cell lines differing in the expression level of the main drug efflux transporters P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and BCRP. The lowest HY accumulation, and consequently the highest resistance to HY-PDT, was found in cells overexpressing BCRP. Moreover, pretreatment with BCRP inhibitor Ko143 significantly in-creased HY accumulation and sensitized cells to HY-PDT. Therefore, our findings represent direct evidence that BCRP is the nemesis of HY accumulation and toxicity of HY-PDT. Thus, we should emphasize that individualized screening for BCRP expression and activity may represent a useful tool for prediction of HY-mediated photo-dynamic diagnosis (PDD) or PDT effectiveness.
    1. Introduction
    Hypericin (HY) is a secondary metabolite synthesized by plants of the genus Hypericum, especially Hypericum perforatum L. (St. John’s wort). Because of its powerful photosensitizing properties, HY is re-garded as the most potent naturally-occurring photosensitizer (PS) that is applicable in photodynamic therapy (PDT) and photodynamic diag-nosis (PDD) of various cancers [reviewed in 1]. After the accumulation of HY in malignant tissue and its activation by light irradiation, hy-pericin-mediated photodynamic therapy (HY-PDT) leads to necrosis [2–4], apoptosis [4,5], autophagy-associated cell death [6,7] or even to immunogenic cell death [8]. The outcome of HY-PDT depends on multiple factors including the intracellular concentration of HY, in-cubation time, irradiation conditions (wavelength of light, fluency rate and light dose) and cell type as well as on the histological origin of the tissue and the oxygen pressure in it [reviewed in 9].