Mechanisms of apoptosis by the tyrphostin AG957 in hematopoietic cells

Alexander Urbano, Gullu Gorgun, Francine Foss

Research output: Contribution to journalArticle

16 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Apoptosis
Phosphorylation
Phosphotransferases
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia
Phosphatidylinositol 3-Kinase
Tyrphostins
Cytochromes c1
T-cells
Caspase 9
Growth
Cytochromes c
tyrphostin AG957
Protein-Tyrosine Kinases
Stem Cells
Down-Regulation
Cells
Association reactions
T-Lymphocytes
Cell Line

Keywords

  • Akt
  • Apoptosis
  • BAD
  • Leukemia
  • Tyrphostins

ASJC Scopus subject areas

  • Pharmacology

Cite this

Mechanisms of apoptosis by the tyrphostin AG957 in hematopoietic cells. / Urbano, Alexander; Gorgun, Gullu; Foss, Francine.

In: Biochemical Pharmacology, Vol. 63, No. 4, 15.02.2002, p. 689-692.

Research output: Contribution to journalArticle

Urbano, Alexander ; Gorgun, Gullu ; Foss, Francine. / Mechanisms of apoptosis by the tyrphostin AG957 in hematopoietic cells. In: Biochemical Pharmacology. 2002 ; Vol. 63, No. 4. pp. 689-692.
@article{8cb1ee0f91bf497c8328f1faf5f48657,
title = "Mechanisms of apoptosis by the tyrphostin AG957 in hematopoietic cells",
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.",
keywords = "Akt, Apoptosis, BAD, Leukemia, Tyrphostins",
author = "Alexander Urbano and Gullu Gorgun and Francine Foss",
year = "2002",
month = "2",
day = "15",
doi = "10.1016/S0006-2952(01)00916-9",
language = "English (US)",
volume = "63",
pages = "689--692",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "4",

}

TY - JOUR

T1 - Mechanisms of apoptosis by the tyrphostin AG957 in hematopoietic cells

AU - Urbano, Alexander

AU - Gorgun, Gullu

AU - Foss, Francine

PY - 2002/2/15

Y1 - 2002/2/15

N2 - 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.

AB - 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.

KW - Akt

KW - Apoptosis

KW - BAD

KW - Leukemia

KW - Tyrphostins

UR - http://www.scopus.com/inward/record.url?scp=0037085016&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037085016&partnerID=8YFLogxK

U2 - 10.1016/S0006-2952(01)00916-9

DO - 10.1016/S0006-2952(01)00916-9

M3 - Article

VL - 63

SP - 689

EP - 692

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 4

ER -