Photoactivation enhances the mitochondrial toxicity of the cationic rhodacyanine MKT-077.

Abstract

In this study, the mitochondrial phototoxicity of the cationic rhodacyanine MKT-077 was investigated by comparing its effects on the inhibition of mitochondrial respiration and the structural integrity of mitochondrial DNA (mtDNA) in the presence and absence of added high-intensity visible light (7.5 J/cm2). Results indicate that photoirradiation significantly enhances the mitochondrial toxicity of MKT-077 at both the biochemical and DNA levels. For example, the concentration of MKT-077 required to achieve one-half maximal inhibition of ADP-stimulated respiration was observed to be 6-fold lower in the presence versus absence of high-intensity light (one-half maximal inhibition at 2.5 versus 15 microg MKT-077/ mg, respectively). In addition, photoirradiation produced a 25-fold increase in inhibition of succinate-cytochrome c reductase activity by MKT-077 (one-half maximal inhibition at 2 versus 50 microg MKT-077/ml, +/-light, respectively) and a 6-fold increase in inhibition of cytochrome oxidase activity (one-half maximal inhibition at 5 versus 30 microg MKT-077/ml, +/-light, respectively). Furthermore, the combination of 25 microg/ml MKT-077 and 7.5 J/cm2 visible light caused significant degradation of mtDNA in isolated rat liver mitochondria, whereas the same concentration of dye in the absence of light had only a modest effect on mtDNA. Evaluation of light-induced MKT-077 lipid peroxidation in mitochondrial membrane fragments by the thiobarbituric acid test and by measurement of nonrespiratory-linked oxygen uptake suggests that mitochondrial phototoxicity by MKT-077 may be the result of lipid peroxidation via reactive oxygen species. These results have important implications with regard to the potential use of MKT-077 in photochemotherapy.

• Authors: J S Modica-Napolitano, B T Brunelli, K Koya, L B Chen
• Journal: Cancer research (Cancer Res) Vol. 58 Issue 1 Pg. 71-5 (Jan 01 1998) ISSN: 0008-5472 [Print] United States
• PMID: 9426060 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• DNA, Mitochondrial
• Pyridines
• Thiazoles
• MKT 077
• Succinic Acid
• NADH Dehydrogenase
• Electron Transport Complex IV

Topics

• Animals
• Antineoplastic Agents (pharmacology, radiation effects)
• Cells, Cultured
• DNA, Mitochondrial (drug effects)
• Electron Transport Complex IV (metabolism)
• Haplorhini
• Light
• Lipid Peroxidation (drug effects)
• Male
• Mitochondria (drug effects, genetics, physiology)
• NADH Dehydrogenase (metabolism)
• Oxygen Consumption (drug effects)
• Pyridines (pharmacology, radiation effects)
• Rats
• Rats, Sprague-Dawley
• Succinic Acid (metabolism)
• Thiazoles (pharmacology, radiation effects)