Mitochondrial DNA is a direct target of anti-cancer anthracycline drugs
- University of Oxford, Nuffield Department of Obstetrics and Gynaecology, Womens Centre, John Radcliffe Hospital, Oxford OX3 9DU (United Kingdom)
The anthracyclines, such as doxorubicin (DXR), are potent anti-cancer drugs but they are limited by their clinical toxicity. The mechanisms involved remain poorly understood partly because of the difficulty in determining sub-cellular drug localisation. Using a novel method utilising the fluorescent DNA dye PicoGreen, we found that anthracyclines intercalated not only into nuclear DNA but also mitochondrial DNA (mtDNA). Intercalation of mtDNA by anthracyclines may thus contribute to the marked mitochondrial toxicity associated with these drugs. By contrast, ethidium bromide intercalated exclusively into mtDNA, without interacting with nuclear DNA, thereby explaining why mtDNA is the main target for ethidium. By exploiting PicoGreen quenching we also developed a novel assay for quantification of mtDNA levels by flow-cytometry, an approach which should be useful for studies of mitochondrial dysfunction. In summary our PicoGreen assay should be useful to study drug/DNA interactions within live cells, and facilitate therapeutic drug monitoring and kinetic studies in cancer patients.
- OSTI ID:
- 21255833
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 378, Issue 3; Other Information: DOI: 10.1016/j.bbrc.2008.11.059; PII: S0006-291X(08)02253-5; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
Similar Records
The effect of ethidium bromide and chloramphenicol on mitochondrial biogenesis in primary human fibroblasts
The Involvement of Mitochondrial Membrane Potential in Cross-Resistance Between Radiation and Docetaxel