A new cellular target for mitomycin C: a case for mitochondrial DNA.
Mitomycin C (MMC) is an anticancer, antibiotic that is currently used clinically against a wide variety of tumors. Nuclear DNA is regarded as the primary cellular target for mitomycin's toxicity. In this study, the effect of MMC on mitochondrial DNA was tested both in vitro and in vivo. EMT6 mouse mammary carcinoma cells were treated with MMC and conformational changes in their mitochondrial DNA were determined as a measure of mitochondrial DNA damage. A dose-dependent relationship was observed between MMC treatment dosages and mitochondrial DNA damage. Liver tissue mitochondria from Balb/c mice treated with MMC were assayed for mitochondrial integrity. Mitochondrial integrity was lowered in the MMC-treated animals. Liver tissue adenosine triphosphate (ATP) levels were also shown to be significantly decreased in these same animals. We also show that MMC can be activated by mitochondria. These studies provide strong evidence that mitochondrial DNA is a target for MMC and that this interaction has a biochemical consequence that could prove toxic.
Pritsos
C A
CA
Department of Nutrition, University of Nevada, Reno 89557, USA. pritsos@med.unr.edu
Briggs
L A
LA
Gustafson
D L
DL
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D004272:DNA, Mitochondrial / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D016685:Mitomycin / Q000494:pharmacology*; D009690:Nucleic Acid Conformation; D010101:Oxygen Consumption / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D004272:DNA, Mitochondrial; D016685:Mitomycin; D000255:Adenosine Triphosphate