Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial.
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 apoptosis. Similarly, primary acute 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.
Sampath
Deepa
D
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Cortes
Jorge
J
Estrov
Zeev
Z
Du
Min
M
Shi
Zheng
Z
Andreeff
Michael
M
Gandhi
Varsha
V
Plunkett
William
W
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001752:Blast Crisis / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D003561:Cytarabine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004249:DNA Damage; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D010599:Pharmacokinetics; D010766:Phosphorylation; D010865:Pilot Projects; D011494:Protein Kinases / Q000378:metabolism; D016879:Salvage Therapy / Q000379:methods; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured
D003561:Cytarabine; C054852:7-hydroxystaurosporine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D051058:Oncogene Protein v-akt; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D048031:JNK Mitogen-Activated Protein Kinases; D019311:Staurosporine