title: Sonodynamic and photodynamic mechanisms of action of the novel hypocrellin sonosensitizer, SL017: mitochondrial cell death is attenuated by 11, 12-epoxyeicosatrienoic acid.
abstract: Development of sonosensitizers for sonodynamic therapy (SDT) which selectively target abnormal cells can limit undesired side effects in chemotherapeutic applications. Hypocrellin-B (HB) derivatives are low molecular weight compounds which belong to the perylenequinone family of photosensitizing and sonosensitizing compounds. In this study, we investigate the cytotoxic mechanisms of a novel HB-derived photo- and sonosensitizer, SL017. Human fibroblast WI-38 cells were treated with SL017 (0 μM, 0.1 μM or 10 μM) and subjected to photodynamic therapy (PDT) or SDT. Studies demonstrate that maximal uptake of SL017 occurs within 30 min, with a mitochondrial subcellular localization. Activation of SL017 by either visible light or ultrasound resulted in significant increases in reactive oxygen species (ROS) production as measured by CM-H2-DCFDA (5-(and-6)-chloromethyl-2'7'-dichlorodihydrofluorescein diacetate acetyl ester). Co-administration of the antioxidant, ascorbic acid, attenuated ROS production. Low concentrations of SL017 (100 nM) induced a rapid (<90 s) loss of mitochondrial membrane potential (ΔΨm). Epoxyeicosatrienoic acids (EETs), cytochrome P450-derived metabolites of arachidonic acid (AA) involved in maintaining homeostasis and protection against cell injury, were able to attenuate loss of ΔΨm, however ascorbic acid was not. SL017 treatment resulted in increased mitochondrial fragmentation which followed loss of ΔΨm. Our studies demonstrate that SL017 targets mitochondria, triggering collapse of mitochondrial membrane potential, generates ROS and subsequently results in mitochondrial fragmentation.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, T6G 2N8, Canada.
authors.forename: Haitham E
authors.initials: HE
authors.lastname: El-Sikhry
authors.forename: Gerald G
authors.initials: GG
authors.lastname: Miller
authors.forename: Madi R
authors.initials: MR
authors.lastname: Madiyalakan
authors.forename: John M
authors.initials: JM
authors.lastname: Seubert
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010569:Perylene / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010778:Photochemotherapy / Q000379:methods; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology*; D011809:Quinones / Q000008:administration & dosage / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014464:Ultrasonic Therapy / Q000379:methods
chemical_list: C569373:2-(N,N-dimethylaminopropyl)amino-15-acetyl-3,10-dihydroxy-6,7,11-trimethoxy-14-methyl-15-H-cyclohepta(ghi)perylene-4,9-dione; D017319:Photosensitizing Agents; D011809:Quinones; D017382:Reactive Oxygen Species; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D010569:Perylene; D015126:8,11,14-Eicosatrienoic Acid; C064522:hypocrellin B