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Tufts University, Department of Biology, Medford, Massachusetts 02155 [J. S. M-N., B. T. B.], and Dana-Farber Cancer Institute, Division of Cellular and Molecular Biology, Harvard Medical School, Boston, Massachusetts 02115 [K. K., E. W., Y. L., L. B. C.]
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 µg MKT-077/mg protein), as compared to the human colon carcinoma cell line, CX-1 (4 µg 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 µg/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.
1 To whom requests for reprints should be addressed, at Department of Biology, Merrimack College, North Andover, MA 01845. Phone: (508) 837-5000, ext. 4459.
Received 6/ 7/95. Accepted 11/17/95.
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