The anti-psoriatic drug anthralin accumulates in keratinocyte mitochondria, dissipates mitochondrial membrane potential, and induces apoptosis through a pathway dependent on respiratory competent mitochondria

FASEB J. 2005 Jun;19(8):1012-4. doi: 10.1096/fj.04-2664fje. Epub 2005 Mar 31.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthralin / analysis
  • Anthralin / metabolism*
  • Anthralin / pharmacology*
  • Anti-Inflammatory Agents
  • Apoptosis / drug effects*
  • Caspase 3
  • Caspases / metabolism
  • Cells, Cultured
  • Cytochromes c / metabolism
  • DNA Fragmentation / drug effects
  • DNA, Mitochondrial / physiology
  • Electron Transport
  • Enzyme Activation / drug effects
  • Fluorescent Antibody Technique
  • Humans
  • Keratinocytes / chemistry
  • Keratinocytes / drug effects
  • Keratinocytes / ultrastructure*
  • Membrane Potentials / drug effects
  • Mitochondria / chemistry
  • Mitochondria / drug effects*
  • Mitochondria / physiology*
  • Oxygen Consumption
  • Psoriasis / drug therapy
  • Ubiquinone / metabolism

Substances

  • Anti-Inflammatory Agents
  • DNA, Mitochondrial
  • Ubiquinone
  • Cytochromes c
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Anthralin