The antipsoriatic drug anthralin accumulates in keratinocyte mitochondria, dissipates mitochondrial membrane potential, and induces apoptosis through a pathway dependent on respiratory competent mitochondria
- 31 March 2005
- journal article
- fj express-summaries
- Published by Wiley in The FASEB Journal
- Vol. 19 (8), 1012-1014
- https://doi.org/10.1096/fj.04-2664fje
Abstract
Anthralin is a potent topical drug, inducing clearance of psoriatic plaques. Anthralin disrupts mitochondrial function and structure, but its mechanism of action remains undefined. This study aimed to determine whether anthralin induced keratinocyte apoptosis as well as to investigate molecular mechanisms and the role of mitochondria. We studied human keratinocytes and human 143B rho(0) cells, which lack mitochondrial DNA and a functional respiratory chain. We show that anthralin disrupts mitochondrial membrane potential (DeltaPsim) and causes endogenous cytochrome c release, resulting in the activation of caspase-3 and characteristic morphological changes of apoptosis. Disruption of DeltaPsim and cytochrome c release were independent of mitochondrial permeability transition or caspase activation. Human 143B rho(0) cells were resistant to anthralin-induced cell death, disruption of DeltaPsim, and cytochrome c release compared with the isogenic 143B rho+ cell line. Using the intrinsic fluorescence of anthralin, rapid accumulation within mitochondria was observed independent of DeltaPsim. Using assays that measure individual respiratory chain complexes, we show that anthralin specifically interacts with ubiquinone pool. These data indicate that anthralin induces apoptosis through a novel mitochondrial pathway dependent on oxidative respiration and involving electron transfer with the ubiquinone pool. These studies identify keratinocyte apoptosis as a potentially important mechanism involved in the clearance of psoriasis.Keywords
Funding Information
- Wellcome Trust (061178)
- British Skin Foundation
This publication has 48 references indexed in Scilit:
- The Tumor Suppressor cybL, a Component of the Respiratory Chain, Mediates Apoptosis InductionMolecular Biology of the Cell, 2003
- Identification of Aberrantly Regulated Genes in Diseased Skin Using the cDNA Differential Display TechniqueJournal of Investigative Dermatology, 1997
- An Evaluation of the Measurement of the Activities of Complexes I-IV in the Respiratory Chain of Human Skeletal Muscle MitochondriaBiochemical Medicine and Metabolic Biology, 1994
- Succinate-cytochrome c reductase: assessment of its value in the investigation of defects of the respiratory chainBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1993
- New Colorimetric Cytotoxicity Assay for Anticancer-Drug ScreeningJNCI Journal of the National Cancer Institute, 1990
- Electron microscopic observations of dyskeratosis, apoptosis, colloid bodies and fibrillar degeneration after skin irritation with dithranolJournal of Cutaneous Pathology, 1990
- Mitochondrial ring‐phenomenon of keratinocytes in psoriasis vulgaris after dithranol therapyJournal of Cutaneous Pathology, 1987
- Ultrastructural Changes in Psoriatic Epidermis Following Anthralin TreatmentJournal of Cutaneous Pathology, 1974
- Mitotic Index of Psoriatic Lesions Treated with Anthralin, Glucocorticosteriod and Occlusion OnlyJournal of Investigative Dermatology, 1970
- Petite Mutants induced in Yeast by Dithranol (1,8,9-trihydroxyanthracene), an Important Therapeutic Agent against PsoriasisNature, 1967