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-farnesylation, 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 used for these studies. We report that BZA-5B treated cells show an increased resistance to cisplatin. BZA-5B treatment decreased the number of cells showing in situ DNA fragmentation and increased cell viability and clonogenic survival after cisplatin treatment. Further experiments showed that cisplatin induction of the immediate early genes c-jun and p21cip1 was not affected by BZA-5B. Finally, we show that cisplatin causes only weak activation of Jun N-terminal kinase (JNK) in a human melanoma cell line. We conclude that inhibition of Ras function decreases the sensitivity of human melanoma cells to cisplatin-induced cell death.
Fokstuen
T
T
Department of Oncology and Pathology, Karolinska Institute and Hospital, Stockholm, Sweden.
Rabo
Y B
YB
Zhou
J N
JN
Karlson
J
J
Platz
A
A
Shoshan
M C
MC
Hansson
J
J
Linder
S
S
D019883:Alkyl and Aryl Transferases; D017209:Apoptosis; D001569:Benzodiazepines / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D053938:DNA Fragmentation; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase; D011905:Genes, ras; D006801:Humans; D008545:Melanoma; D009842:Oligopeptides / Q000494:pharmacology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors*; D014166:Transferases / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
C090156:BZA 5B; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D001569:Benzodiazepines; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D002945:Cisplatin