This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dalton, M. B. Articles by Sinensky, M. Search for Related Content PubMed PubMed Citation Articles by Dalton, M. B. Articles by Sinensky, M.

The Farnesyl Protein Transferase Inhibitor BZA-5B Blocks Farnesylation of Nuclear Lamins and p21^ras but Does Not Affect Their Function or Localization¹

Eleanor Roosevelt Institute, Denver, Colorado 80206 [M. B. D., K. S. F., H. A. B., L. D., A. K., M. S.], and Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado 80262 [R. M. E.]

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 p21^ras 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 p21^ras. At a concentration in excess of 25 µM, 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 p21^ras, and p21^ras-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.

¹ This work was supported by Grant BE29 (to M. S.) from the American Cancer Society and Grant HD 07197 (to M. B. D.) from the Cancer League of Colorado and the NIH. L. D. was supported by the Brooks Trust of the Colorado Division of the American Cancer Society and by Cancer Education Grant CA 49981 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Eleanor Roosevelt Institute, 1899 Gaylord Street, Denver, CO 80206.

Received 3/20/95. Accepted 5/30/95.

This article has been cited by other articles:

				J. E. Lancet, I. Gojo, J. Gotlib, E. J. Feldman, J. Greer, J. L. Liesveld, L. M. Bruzek, L. Morris, Y. Park, A. A. Adjei, et al. A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia Blood, February 15, 2007; 109(4): 1387 - 1394. [Abstract] [Full Text] [PDF]

				A. E. Rusinol and M. S. Sinensky Farnesylated lamins, progeroid syndromes and farnesyl transferase inhibitors. J. Cell Sci., August 15, 2006; 119(Pt 16): 3265 - 3272. [Abstract] [Full Text] [PDF]

				S. Einav and J. S. Glenn Prenylation inhibitors: a novel class of antiviral agents J. Antimicrob. Chemother., December 1, 2003; 52(6): 883 - 886. [Abstract] [Full Text] [PDF]

				C. P. Maske, M. S. Hollinshead, N. C. Higbee, M. O. Bergo, S. G. Young, and D. J. Vaux A carboxyl-terminal interaction of lamin B1 is dependent on the CAAX endoprotease Rce1 and carboxymethylation J. Cell Biol., September 29, 2003; 162(7): 1223 - 1232. [Abstract] [Full Text] [PDF]

				B. B. Bordier, P. L. Marion, K. Ohashi, M. A. Kay, H. B. Greenberg, J. L. Casey, and J. S. Glenn A Prenylation Inhibitor Prevents Production of Infectious Hepatitis Delta Virus Particles J. Virol., September 11, 2002; 76(20): 10465 - 10472. [Abstract] [Full Text] [PDF]

				S. Sharma, N. Kemeny, D. P. Kelsen, D. Ilson, E. O'Reilly, S. Zaknoen, C. Baum, P. Statkevich, E. Hollywood, Y. Zhu, et al. A phase II trial of farnesyl protein transferase inhibitor SCH 66336, given by twice-daily oral administration, in patients with metastatic colorectal cancer refractory to 5-fluorouracil and irinotecan Ann. Onc., July 1, 2002; 13(7): 1067 - 1071. [Abstract] [Full Text] [PDF]

				R. D. Moir, M. Yoon, S. Khuon, and R. D. Goldman Nuclear Lamins a and B1: Different Pathways of Assembly during Nuclear Envelope Formation in Living Cells J. Cell Biol., December 11, 2000; 151(6): 1155 - 1168. [Abstract] [Full Text] [PDF]

				C. W. M. Reuter, M. A. Morgan, and L. Bergmann Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies? Blood, September 1, 2000; 96(5): 1655 - 1669. [Abstract] [Full Text] [PDF]

				S. Yalovsky, M. Rodríguez-Concepción, K. Bracha, G. Toledo-Ortiz, and W. Gruissem Prenylation of the Floral Transcription Factor APETALA1 Modulates Its Function PLANT CELL, August 1, 2000; 12(8): 1257 - 1266. [Abstract] [Full Text]

				J. S. Russell, F. F. Lang, T. Huet, M. Janicot, S. Chada, D. R. Wilson, and P. J. Tofilon Radiosensitization of Human Tumor Cell Lines Induced by the Adenovirus-mediated Expression of an Anti-Ras Single-Chain Antibody Fragment Cancer Res., October 1, 1999; 59(20): 5239 - 5244. [Abstract] [Full Text] [PDF]

				P. A. Theodoropoulos, H. Polioudaki, O. Kostaki, S. P. Derdas, V. Georgoulias, C. Dargemont, and S. D. Georgatos Taxol Affects Nuclear Lamina and Pore Complex Organization and Inhibits Import of Karyophilic Proteins into the Cell Nucleus Cancer Res., September 1, 1999; 59(18): 4625 - 4633. [Abstract] [Full Text] [PDF]

				W. Du, P. F. Lebowitz, and G. C. Prendergast Elevation of {{alpha}}2(I) Collagen, a Suppressor of Ras Transformation, Is Required for Stable Phenotypic Reversion by Farnesyltransferase Inhibitors Cancer Res., May 1, 1999; 59(9): 2059 - 2063. [Abstract] [Full Text] [PDF]

				T. E. Graham, J. R. Pfeiffer, R. J. Lee, D. F. Kusewitt, A. M. Martinez, T. Foutz, B. S. Wilson, and J. M. Oliver MEK and ERK Activation in Ras-Disabled RBL-2H3 Mast Cells and Novel Roles for Geranylgeranylated and Farnesylated Proteins in Fc{epsilon}RI-Mediated Signaling J. Immunol., December 15, 1998; 161(12): 6733 - 6744. [Abstract] [Full Text] [PDF]

				J. S. Glenn, J. C. Marsters Jr., and H. B. Greenberg Use of a Prenylation Inhibitor as a Novel Antiviral Agent J. Virol., November 1, 1998; 72(11): 9303 - 9306. [Abstract] [Full Text] [PDF]

				F. Kilic, M. B. Dalton, S. K. Burrell, J. P. Mayer, S. D. Patterson, and M. Sinensky In Vitro Assay and Characterization of the Farnesylation-dependent Prelamin A Endoprotease J. Biol. Chem., February 21, 1997; 272(8): 5298 - 5304. [Abstract] [Full Text] [PDF]