Inhibition of Protein Glycosylation and Selective Cytotoxicity toward Virally Transformed Fibroblasts Caused by B3‐Tunicamycin

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Abstract
The biological effect of B3‐tunicamycin, the only known homologue of tunicamycin which contains a saturated fatty‐acid side chain, was examined using chick embryo fibroblasts, a mouse fibroblastic line (3T3) and a virally transformed mouse fibroblastic line (SV40–3T3). This homologue inhibited the transfer of N‐acetylglucosamine 1‐phosphate from UDP‐N‐acetylglucosamine to dolichyl phosphate, catalyzed by microsomes from chick liver or from cultured mouse fibroblasts. B3‐tunicamycin also inhibited the incorporation of mannose into glycoproteins synthesized by chick or mouse fibroblasts. Incorporation of the amino acids proline and tyrosine was inhibited by B3‐tunicamycin to a lesser extent than the incorporation of mannose. The mannose incorporation into glycoproteins synthesized by virally transformed cells was inhibited by B3‐tunicamycin to a higher degree than what was achieved in the nontransformed lines or in the chick primary fibroblats. When the activity of B3‐tunicamycin as an inhibitor of protein glycosylation was compared to other homologues of tunicamycin, it was found to be the most active. This homologue caused complete (more than 95%) inhibition of protein glycosylation at a concentration of 50 ng/ml in chick and in mouse fibroblasts and at a concentration of 10 ng/ml in transformed mouse fibroblasts. When the cytotoxic activities of tunicamycin homologues were examined on nontransformed and virally transformed 3T3 cells, it was found that B3‐tunicamycin displayed the highest selective cytotoxicity toward the transformed cells. When transformed fibroblasts (105 cells/plate) were treated with B3‐tunicamycin (100 ng/ml) for 48 h, complete cell death was observed. The viability and the proliferative activity of the nontransformed fibroblast were normal even when treated with concentrations up to 500 ng/ml of B3‐tunicamycin. This suggests that B3‐tunicamycin may be a suitable candidate for studies of tumor growth in animals.