Assessment of the significance of mitochondrial DNA damage by chemotherapeutic agents.
The pathways which are activated following damage to nuclear DNA in cancer cells are well understood. There is evidence that treatment with several chemotherapeutic agents may result in damage to mitochondrial DNA. This study investigated the contribution of mitochondrial DNA to cytotoxicity of DNA-interactive agents. To understand the significance of drug interactions with mitochondrial DNA, we investigated A549 non-small cell lung cancer cell lines and their rho0 derivatives in which mitochondrial DNA has been eradicated. The parental cell line showed increased sensitivity to the anthracycline daunorubicin when compared with the A549 rho0 line. In addition, the A549 rho0 line was resistant to the rhodacyanine derivative, MKT-077, which has been shown to interact with mitochondrial DNA. Southern blotting demonstrated that MKT-077 mediated damage to mitochondrial but not nuclear DNA. Restoration of mitochondrial DNA by formation of cybrids restored sensitivity to these agents. The mitochondrial DNA damage, following treatment of A549 rho0 cells with MKT-077, resulted in G2 arrest which was not mediated by expression of p53. Mitochondrial DNA is a critical target for MKT-077 and daunorubicin, and is a potential target for novel chemotherapeutic agents.
Lo
Soo
S
Department of Oncology, Royal Free and University College Medical School, University College London, London W1P 8BT, UK.
Tolner
Berend
B
Taanman
Jan-Willem
JW
Cooper
J Mark
JM
Gu
Mei
M
Hartley
John A
JA
Schapira
Anthony H V
AH
Hochhauser
Daniel
D
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015139:Blotting, Southern; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003630:Daunorubicin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D020128:Inhibitory Concentration 50; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D018435:ATP Binding Cassette Transporter, Subfamily B; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D011725:Pyridines; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; C097880:MKT 077; D045304:Cytochromes c; D004250:DNA Topoisomerases, Type II; D003630:Daunorubicin