Selective damage to carcinoma mitochondria by the rhodacyanine MKT-077.
We investigated the mitochondrial toxicity of the lipophilic cation, MKT-077, and the role of mitochondria in selective malignant cell killing by this compound by examining the effect of MKT-077 on mitochondrial structure and function in treated cells and in isolated organelles. Results of this study demonstrate changes in mitochondrial ultrastructure that are induced by MKT-077 treatment in carcinoma cells but not in similarly treated normal epithelial cells. In addition, MKT-077 was found to inhibit respiratory activity in isolated intact mitochondria and electron transport activity in freeze-thawed mitochondrial membrane fragments in a dose-dependent manner. The concentration of MKT-077 necessary to obtain half-maximal inhibition of ADP-stimulated respiration was approximately 4-fold greater in mitochondria isolated from cells of the normal epithelial cell line, CV-1 (15 micrograms MKT-077/mg protein), as compared to the human colon carcinoma cell line, CX-1 (4 micrograms MKT-077/mg protein). Further, the data show a selective loss of mitochondrial DNA in CX-1 and CRL1420 cells (carcinoma) but not CV-1 cells (normal epithelial) treated with 3 microgram/ml MKT-077 for up to 3 days. Under the same conditions, nuclear DNA was unaffected in all three cell lines. The sensitivity of the cell lines tested to mitochondrial damage by MKT-077 correlates well with their sensitivity to cytotoxicity by MKT-077. These results demonstrate selective mitochondrial damage by MKT-077 at the cellular, biochemical, and molecular levels and suggest that selective effects on mitochondrial structure and function may provide a basis for the selective malignant cell killing exhibited by this compound.
Modica-Napolitano
J S
JS
Tufts University, Department of Biology, Medford, Massachusetts 02155, USA.
Koya
K
K
Weisberg
E
E
Brunelli
B T
BT
Li
Y
Y
Chen
L B
LB
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004272:DNA, Mitochondrial / Q000187:drug effects; D004579:Electron Transport / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects; D006801:Humans; D008297:Male; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000648:ultrastructure*; D010101:Oxygen Consumption / Q000187:drug effects; D011725:Pyridines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000633:toxicity*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D011725:Pyridines; D013844:Thiazoles; C097880:MKT 077