Cytotoxicity of farnesyltransferase inhibitors in lymphoid cells mediated by MAPK pathway inhibition and Bim up-regulation

Husheng Ding, Jennifer S McDonald, Paula A. Schneider, Kevin L. Peterson, X. Wei Meng, Haiming Dai, Thomas Elmer Witzig, Scott H Kaufmann

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The mechanism of cytotoxicity of farnesyltransferase inhibitors is incompletely understood and seems to vary depending on the cell type. To identify potential determinants of sensitivity or resistance for study in the accompanying clinical trial (Witzig et al., page 4882), we examined the mechanism of cytotoxicity of tipifarnib in human lymphoid cell lines. Based on initial experiments showing that Jurkat variants lacking Fas-associated death domain or procaspase-8 undergo tipifarnib-induced apoptosis, whereas cells lacking caspase-9 or overexpressing Bcl-2 do not, we examined changes in Bcl-2 family members. Tipifarnib caused dose-dependent upregulation of Bim in lymphoid cell lines (Jurkat, Molt3, H9, DoHH2, and RL) that undergo tipifarnib-induced apoptosis but not in lines (SKW6.4 and Hs445) that resist tipifarnib-induced apoptosis. Further analysis demonstrated that increased Bim levels reflect inhibition of signaling from c-Raf to MEK1/2 and ERK1/2. Additional experiments showed that downregulation of the Ras guanine nucleotide exchange factor RasGRP1 diminished tipifarnib sensitivity, suggesting that H-Ras or N-Ras is a critical farnesylation target upstream of c-Raf in lymphoid cells. These results not only trace a pathway through c-Raf to Bim that contributes to tipifarnib cytotoxicity in human lymphoid cells but also identify potential determinants of sensitivity to this agent.

Original languageEnglish (US)
Pages (from-to)4872-4881
Number of pages10
JournalBlood
Volume118
Issue number18
DOIs
StatePublished - Nov 3 2011

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tipifarnib
Farnesyltranstransferase
Cytotoxicity
Up-Regulation
Lymphocytes
Apoptosis
ras Guanine Nucleotide Exchange Factors
Cells
Prenylation
Cell Line
Caspase 9
Caspase 8
Inhibition (Psychology)
Down-Regulation
Experiments
Clinical Trials

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Cytotoxicity of farnesyltransferase inhibitors in lymphoid cells mediated by MAPK pathway inhibition and Bim up-regulation. / Ding, Husheng; McDonald, Jennifer S; Schneider, Paula A.; Peterson, Kevin L.; Meng, X. Wei; Dai, Haiming; Witzig, Thomas Elmer; Kaufmann, Scott H.

In: Blood, Vol. 118, No. 18, 03.11.2011, p. 4872-4881.

Research output: Contribution to journalArticle

Ding, Husheng ; McDonald, Jennifer S ; Schneider, Paula A. ; Peterson, Kevin L. ; Meng, X. Wei ; Dai, Haiming ; Witzig, Thomas Elmer ; Kaufmann, Scott H. / Cytotoxicity of farnesyltransferase inhibitors in lymphoid cells mediated by MAPK pathway inhibition and Bim up-regulation. In: Blood. 2011 ; Vol. 118, No. 18. pp. 4872-4881.
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