THE RAS FARNESYLATION INHIBITOR BZA-5B INCREASES THE RESISTANCE TO CISPLATIN IN A HUMAN-MELANOMA CELL-LINE

Ras proteins have been implicated in transducing cellular responses to DNA damaging agents. We used BZA-5B, an inhibitor of Ras-farnesylatio n, to examine the role of Ras in cellular sensitivity to cisplatin. A human melanoma cell line (224) with a Gln61Arg mutation in N-ras was u sed for these studies. We report that BZA-5B treated cells show an inc reased resistance to cisplatin. BZA-5B treatment decreased the number of cells showing in situ DNA fragmentation and increased cell viabilit y and clonogenic survival after cisplatin treatment Further experiment s showed that cisplatin induction of the immediate early genes c-jun a nd p21(cip1) was not affected by BZA-5B. Finally, we show that cisplat in causes only weak activation of Jun N-terminal kinase (JNK) in it hu man melanoma cell line. We conclude that inhibition of Ras function de creases the sensitivity of human melanoma cells to cisplatin-induced c ell death.