Selective cytotoxicity of tunicamycin for transformed cells.

Abstract

AbstractWe have studied the effects of tunicamycin, an inhibitor of dolichol pyrophosphate‐dependent glycosylation of proteins, on the viability of transformed and non‐transformed fibroblasts in culture. We have shown that a low concentration of tunicamycin (0.05 μg/ml or 5 × 10−8 M) is cytotoxic toward a variety of transformed cell lines, including virally or chemically transformed fibroblasts from chick embryo, rat kidney, human lung, and mouse. The corresponding non‐transformed cell lines were resistant to the same and a 10‐fold higher concentration of tunicamycin. However, transformed permanent cell lines were also found to be resistant to tunicamycin. The relationship between transformation and tunicamycin cytotoxicity was strengthened by the finding that chick embryo fibroblasts infected by the temperature‐sensitive viral mutants ts68 or T5 are killed by the drug only at the temperature at which transformation is expressed. The LD50 for sensitive transformed cell lines ranged from 0.02 to 0.034 μ/ml tunicamycin. Maximal cytotoxic effects to transformed cells were produced at tunicamycin concentrations which only slightly inhibited protein synthesis in non‐transformed cells (17–22% in 24 h). There was a good correlation between the susceptibility of transformed cells to tunicamycin cytotoxicity and their sensitivity to tunicamycin inhibition of protein glycosylation, 2‐deoxy‐D‐glucose transport, and glucose metabolism. These results indicate that tunicamycin interferes with some cellular process critical for the survival of many transformed cells but not of non‐transformed cells. We speculate that the cytotoxicity of this drug towards transformed cells may result from impaired rates of nutrient transport, although other mechanisms are possible. Tunicamycin may, therefore, be therapeutically useful as an anti‐tumor agent to selectively kill certain types of malignant cells, while sparing non‐transformed cells.