Mechanisms of apoptosis by the tyrphostin AG957 in hematopoietic cells

Alexander Urbano, Gullu Gorgun, Francine Foss

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

AG957 (NSC 654705) is a tyrphostin tyrosine kinase inhibitor that has been demonstrated previously to induce growth arrest in chronic myelogenous leukemia cells by inhibiting p210bcr-abl kinase activity and by stabilizing the association of p210bcr-abl kinase with its signaling adaptor molecules, Shc and Grb2. In previous studies, it has been demonstrated that AG957-associated down-regulation of bcr-abl activates the cytochrome c/Apaf-1/caspase-9 pathway and induces apoptosis in chronic myelogenous leukemia blasts and progenitor cells. While AG957 has been purported to have specificity for the p210bcr-abl kinase, antiproliferative effects of AG957 in normal T-lymphocytes and bcr-abl negative leukemia cells suggest that other targets, such as c-CBL, may be substrates. In this study, we explored the mechanisms of AG957-mediated growth inhibition and apoptosis in the p210bcr-abl negative leukemia cell lines Nalm-6 and Jurkat, and demonstrate that AG957-mediated apoptosis is associated with altered phosphorylation of Akt and BAD, which destabilizes the Bcl-xL/BAD complex and releases the block to apoptosis. We, therefore, propose that AG957 induces apoptosis in bcr-abl negative hematopoietic cells by affecting the phosphorylation state of phosphatidylinositol-3 kinase/Akt.

Original languageEnglish (US)
Pages (from-to)689-692
Number of pages4
JournalBiochemical Pharmacology
Volume63
Issue number4
DOIs
StatePublished - Feb 15 2002

Keywords

  • Akt
  • Apoptosis
  • BAD
  • Leukemia
  • Tyrphostins

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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