The farnesyl protein transferase inhibitor BZA-5B blocks farnesylation of nuclear lamins and p21ras but does not affect their function or localization.
BZA-5B is a peptidomimetic inhibitor of protein farnesylation in mammalian cells. We have examined the specificity of this compound toward inhibition of farnesylation of p21ras and the nuclear lamin proteins, prelamin A and lamin B. We have also used the Raney nickel cleavage technique in conjunction with radio-gas liquid chromatography to assess the ability of this compound to block total protein farnesylation. These studies show that BZA-5B blocks farnesylation of the lamin proteins with an IC50 comparable to that seen for p21ras. At a concentration in excess of 25 microM, BZA-5B inhibits all protein farnesylation in CHO-K1 cells below the limits of detection. Furthermore, we found that after a 2-day exposure to high concentrations of BZA-5B, CHO-K1 cell lines exhibit no loss in sensitivity to inhibition of prenylation by this compound. Yet, despite the potent and general inhibition of protein farnesylation, BZA-5B does not interfere with a variety of cellular functions expected to be farnesylation dependent, including cell growth and viability, assembly of the nuclear lamina, membrane association of p21ras, and p21ras-dependent differentiation of PC-12 cells in response to treatment with nerve growth factor. The maintenance of farnesylation-dependent events in the presence of BZA-5B stands in marked contrast to the inhibition of the oncogenic ras-mediated transformed phenotype that has been observed with this compound and other farnesyl protein transferase inhibitors. This specificity for inhibition of ras transformation by BZA-5B is quite encouraging to its eventual development as an antimalignancy pharmaceutical.
Dalton
M B
MB
Eleanor Roosevelt Institute, Denver, Colorado 80206, USA.
Fantle
K S
KS
Bechtold
H A
HA
DeMaio
L
L
Evans
R M
RM
Krystosek
A
A
Sinensky
M
M
D000310:Adrenal Gland Neoplasms / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D006224:Cricetinae; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects* / Q000502:physiology; D004351:Drug Resistance; D006367:HeLa Cells; D006801:Humans; D034904:Lamin Type A; D034921:Lamin Type B; D034882:Lamins; D008798:Mevalonic Acid / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology; D009687:Nuclear Proteins / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology*; D010673:Pheochromocytoma / Q000378:metabolism; D011498:Protein Precursors / Q000187:drug effects* / Q000378:metabolism; D051381:Rats
D000970:Antineoplastic Agents; C090156:BZA 5B; C493956:CDKN1A protein, human; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D034904:Lamin Type A; D034921:Lamin Type B; D034882:Lamins; D009414:Nerve Growth Factors; D009687:Nuclear Proteins; D009842:Oligopeptides; D011498:Protein Precursors; C090764:prelamin A; D001569:Benzodiazepines; D008798:Mevalonic Acid