The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drug-resistant myeloma tumor cells

S. C E Bolick, T. H. Landowski, D. Boulware, M. M. Oshiro, J. Ohkanda, Andrew Hamilton, S. M. Sebti, W. S. Dalton

Research output: Contribution to journalArticle

Abstract

Mutations of the ras gene are among the most commonly identified transforming events in human cancers, including multiple myeloma. Farnesyltransferase inhibitors (FTI) were developed to prevent Ras processing and induce cancer cell death. Several FTIs are in phase II and one is in phase III clinical trials. Preclinically, most of the focus has been on solid tumors, and the effects of FTIs in multiple myeloma have not been investigated. In this study we examined the cytotoxic activity and inhibition of Ras processing in three myeloma cell lines with differing Ras mutation status. H929 cells with activated N-Ras were more sensitive to FTI-277 treatment than 8226 and U266 cells with activated K-Ras or wild-type Ras, respectively. A combination of FTI-277 and a geranylgeranyltransferase I inhibitor (GGTI)-2166 inhibited K-Ras processing and enhanced cell death in 8226 cells. U266 cells and Bcl-xL transfectants were equally sensitive to FTI-277 treatment. Similarly, 8226 cells selected for resistance to various chemotherapeutic agents, which resulted in either P-glycoprotein overexpression, altered topoisomerase II activity, or elevated glutathione levels, were equally sensitive to FTI-277. These preclinical studies suggest that prenylation inhibitors may represent new therapeutic agents for the treatment of refractory or drug-resistant multiple myeloma.

Original languageEnglish (US)
Pages (from-to)451-457
Number of pages7
JournalLeukemia
Volume17
Issue number2
DOIs
StatePublished - Feb 1 2003

Fingerprint

Farnesyltranstransferase
Transferases
Apoptosis
Multiple Myeloma
Growth
Pharmaceutical Preparations
Neoplasms
Cell Death
Prenylation
Type II DNA Topoisomerase
Phase III Clinical Trials
Mutation
ras Genes
P-Glycoprotein
Glutathione
Cell Line

Keywords

  • Bcl-x
  • Drug resistance
  • Farnesyltransferase inhibitor
  • Myeloma
  • Ras

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

Cite this

Bolick, S. C. E., Landowski, T. H., Boulware, D., Oshiro, M. M., Ohkanda, J., Hamilton, A., ... Dalton, W. S. (2003). The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drug-resistant myeloma tumor cells. Leukemia, 17(2), 451-457. https://doi.org/10.1038/sj.leu.2402832

The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drug-resistant myeloma tumor cells. / Bolick, S. C E; Landowski, T. H.; Boulware, D.; Oshiro, M. M.; Ohkanda, J.; Hamilton, Andrew; Sebti, S. M.; Dalton, W. S.

In: Leukemia, Vol. 17, No. 2, 01.02.2003, p. 451-457.

Research output: Contribution to journalArticle

Bolick, SCE, Landowski, TH, Boulware, D, Oshiro, MM, Ohkanda, J, Hamilton, A, Sebti, SM & Dalton, WS 2003, 'The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drug-resistant myeloma tumor cells', Leukemia, vol. 17, no. 2, pp. 451-457. https://doi.org/10.1038/sj.leu.2402832
Bolick, S. C E ; Landowski, T. H. ; Boulware, D. ; Oshiro, M. M. ; Ohkanda, J. ; Hamilton, Andrew ; Sebti, S. M. ; Dalton, W. S. / The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drug-resistant myeloma tumor cells. In: Leukemia. 2003 ; Vol. 17, No. 2. pp. 451-457.
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