Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial

Deepa Sampath, Jorge Cortes, Zeev Estrov, Min Du, Zheng Shi, Michael Andreeff, Varsha Gandhi, William Plunkett

Research output: Contribution to journalArticle

Abstract

Chk1 and Akt signaling facilitate survival of cells treated with nucleoside analogues. Activation of Chk1 in response to cytarabine (ara-C) induced an S-phase checkpoint characterized by the inhibition of Cdk2, cell cycle arrest, no change in constitutively active Akt, or low-stress kinase signaling in ML-1 cells. However, inhibition of Chk1 by UCN-01 in S-phase-arrested cells resulted in an abrogation of the checkpoint, inhibition of Akt, activation of JNK, and a rapid induction of myelogenous leukemia (AML) blasts exposed to ara-C and UCN-01 demonstrated a selective loss in cloning potential when compared with normal progenitors. Therefore, we evaluated a pilot clinical trial of ara-C in combination with UCN-01 in patients with relapsed AML. Blasts from some patients demonstrated a previously activated Chk1-Cdk2 DNA damage response pathway that decreased during therapy. Constitutively phosphorylated Akt kinase declined on addition of UCN-01 to the ara-C infusion, an action accompanied by an activation of JNK and reduction in absolute AML blast counts. Thus, use of UCN-01 in combination with ara-C decreases Chk1 phosphorylation, inhibits the Akt survival pathway, and activates JNK during the course of therapy, offering a rationale for the cytotoxic action of this combination during AML treatment.

Original languageEnglish (US)
Pages (from-to)2517-2524
Number of pages8
JournalBlood
Volume107
Issue number6
DOIs
StatePublished - Mar 15 2006
Externally publishedYes

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Pharmacodynamics
Cytarabine
Clinical Trials
Chemical activation
Phosphotransferases
S Phase Cell Cycle Checkpoints
Cells
Phosphorylation
Myeloid Leukemia
MAP Kinase Signaling System
Cloning
Cell Cycle Checkpoints
S Phase
Nucleosides
DNA Damage
7-hydroxystaurosporine
In Vitro Techniques
Organism Cloning
Cell Survival
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial. / Sampath, Deepa; Cortes, Jorge; Estrov, Zeev; Du, Min; Shi, Zheng; Andreeff, Michael; Gandhi, Varsha; Plunkett, William.

In: Blood, Vol. 107, No. 6, 15.03.2006, p. 2517-2524.

Research output: Contribution to journalArticle

Sampath, Deepa ; Cortes, Jorge ; Estrov, Zeev ; Du, Min ; Shi, Zheng ; Andreeff, Michael ; Gandhi, Varsha ; Plunkett, William. / Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial. In: Blood. 2006 ; Vol. 107, No. 6. pp. 2517-2524.
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