Abstract
Photosensitizers (PSs) in photodynamic therapy (PDT) are administered systemically with preferential accumulation in malignant cells; however, exposure of non-malignant cells to PS may be clinically relevant if PS molecules affect the pro-apoptotic cascade without illumination. The important PS characteristic is low dark cytotoxicity. Originally, Hypericin (Hyp) as PS displayed minimal dark cytotoxicity and preferential accumulation in tumor cells, however recently, evidence to contrary appeared. The molecular mechanisms underlying Hyp dark toxicity may be due to its interaction with different molecules at the Hyp accumulation sites including mitochondria, and they are not understood in detail. Our previous study demonstrated that in human glioma U87 MG cells, Hyp affected localization of pro-apoptotic Bax and Bak, from Bcl2 family of proteins that are key regulators of apoptosis and mitogenesis. To understand the mechanisms underlying Hyp dark toxicity better, we investigated the Hyp effect on mitochondrial function and cell metabolism in U87 MG and human coronary artery endothelial (HCAEC) cells. We have found that Hyp in HCAEC displayed significant dark cytotoxicity in contrast to U87 MG cells. Further, Hyp significantly affected mitochondria function in U87 MG by turning them towards glycolysis, but it did not have this effect in HCAEC. In addition, in both cell types Hyp in the dark triggered morphological changes in mitochondria and the ER and GA ultrastructure indicative of altered protein synthesis. Lastly, in U87 MG and HCAEC Hyp affected the distribution of Bcl2 and Bax proteins via hydrophobic interaction at their BH1-BH3 domain. Overall, our results indicate that Hyp in the dark had effects at several sub-cellular levels similar to small mitochondria targeting molecules (mitocans), and thus Hyp should be explored as mitocan. Support: EU 7FP PIRG06-GA-2009-256580, CELIM 316310; EU SF ITMS 26240120040; VEGA -1-0111-12, APVV-0134-11 and APVV-0242-11
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