title: Hypericin in the Dark: Foe or Ally in Photodynamic Therapy?
abstract: Photosensitizers (PSs) in photodynamic therapy (PDT) are, in most cases, administered systemically with preferential accumulation in malignant tissues; however, exposure of non-malignant tissues to PS may also be clinically relevant, when PS molecules affect the pro-apoptotic cascade without illumination. Hypericin (Hyp) as PS and its derivatives have long been studied, regarding their photodynamic and photocytotoxic characteristics. Hyp and its derivatives have displayed light-activated antiproliferative and cytotoxic effects in many tumor cell lines without cytotoxicity in the dark. However, light-independent effects of Hyp have emerged. Contrary to the acclaimed Hyp minimal dark cytotoxicity and preferential accumulation in tumor cells, it was recently been shown that non-malignant and malignant cells uptake Hyp at a similar level. In addition, Hyp has displayed light-independent toxicity and anti-proliferative effects in a wide range of concentrations. There are multiple mechanisms underlying Hyp light-independent effects, and we are still missing many details about them. In this paper, we focus on Hyp light-independent effects at several sub-cellular levels-protein distribution and synthesis, organelle ultrastructure and function, and Hyp light-independent effects regarding reactive oxygen species (ROS). We summarize work from our laboratories and that of others to reveal an intricate network of the Hyp light-independent effects. We propose a schematic model of pro- and anti-apoptotic protein dynamics between cell organelles due to Hyp presence without illumination. Based on our model, Hyp can be explored as an adjuvant therapeutic drug in combination with chemo- or radiation cancer therapy.
authors.affiliation: Center for Interdisciplinary Biosciences, PJ Safarik University in Kosice, Kosice 040 01, Slovakia. veronika.huntosova@upjs.sk.
authors.forename: Veronika
authors.initials: V
authors.lastname: Huntosova
authors.affiliation: Department of Biophysics, Faculty of Natural Sciences, PJ Safarik University in Kosice, Kosice 040 01, Slovakia. katarina.stroffekova@upjs.sk.
authors.forename: Katarina
authors.initials: K
authors.lastname: Stroffekova
keywords: BAX; Bcl2; PKC; cancer; endothelial cells; glioma cells; hypericin; oxidative stress