ANTITUMOR-PROMOTING ACTIVITY OF CANVENTOL AND ITS SYNTHETIC ANALOGS THROUGH INHIBITION OF PROTEIN ISOPRENYLATION

Canventol, a synthetic compound, is a new inhibitor of tumor promotion on mouse skin by okadaic acid. We previously reported that canventol acts by inhibiting both protein isoprenylation and tumor necrosis fact or-alpha (TNF-alpha) release. In this study we examined the potencies of 10 newly synthesized canventol analogs through their effect on meva lonate metabolism, and then examined 3 representative analogs for inhi bition of protein isoprenylation. Since canventol in vitro did not dir ectly inhibit farnesyl protein transferase or geranylgeranyl protein t ransferase-I, the effects of canventol and its synthetic analogs on th e fate of [H-3]mevalonate in cells were studied. Canventol at 500 mu M changed the ratio of newly synthesized sterols (cholesterol and latho sterol) to ubiquinones from 0.7 to 8.2 in NIH/3T3 cells which had prev iously been labeled with [H-3]mevalonate, suggesting that the altered pattern of mevalonate metabolism is associated with inhibition of prot ein isoprenylation in the cells. We named this ratio the inhibition of protein isoprenylation index (IPI index). The 10 analogs showed a wid e range of IPI indices. Two analogs, S3 and S9 had effects similar to, or stronger than, canventol. Three analogs, C44, C46 and C47, with lo wer IPI indices, inhibited tumor promotion on mouse skin slightly less than canventol itself did. This study shows that inhibition of protei n isoprenylation in the cells, indicated by an increase in the IPI ind ex, is a new biomarker for estimating inhibition of tumor promotion.