3-amino thioacridone inhibits DNA synthesis and induce DNA damage in T-cell acute lymphoblastic leukemia (T-ALL) in a p16-dependent manner.
In T-cell Acute Lymphocytic Leukemia (T-ALL), the inhibitors of cyclin-dependent kinases (CDK) 4 and 6, p16 and p15, are inactivated almost universally at the DNA, RNA and protein levels. This suggests that CDK-targeting may be an effective therapeutic approach for T-ALL and other cancers. In this study, we tested 3 inhibitors of CDK4, 3-aminothioacridone (3-ATA), thioacridone (TA), and oxindole, for their effects on DNA synthesis and viability in primary T-ALL. Each compound was an effective inhibitor, with overall IC(50)s in similar ranges. In colony formation assay, leukemic cells were approximately 10-fold more sensitive to 3-ATA than normal bone marrow cells. When sorted by G1 protein status of T-ALL, p16(+), p15(+) or pRb(-) samples were significantly less sensitive to 3-ATA and TA, but not to oxindole, than p16(-), p15(-) or pRb(+) samples. There was no relationship of sensitivity with ARF expression. Despite their in vitro function as inhibitors of CDK4, 3-ATA did not inhibit pRb phosphorylation or cause G1 arrest, but did cause DNA damage and result in the induction and phosphorylation of p53. We conclude that 3-ATA efficacy can be predicted by p16 status in T-ALL, but the mechanism of action may be distinct from their in vitro ability to regulate CDK4 kinase activity
Diccianni
Mitchell B
MB
Dept of Pediatrics Hematology/Oncology, University of California, San Diego, Medical Center, 200 W. Arbor Dr., San Diego, CA 92103-8447, USA. mdiccianni@ucsd.edu
Yu
John
J
Meppelink
Gerda
G
de Vries
Marten
M
Shao
Lien
L
Gebauer
Sigrun
S
Shih
Hsien
H
Roberts
William
W
Kilcoin
Neil P
NP
Pullen
Jeanette
J
Carson
Dennis A
DA
Yu
Alice L
AL
D000609:Aminoacridines / Q000494:pharmacology*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis*; D004249:DNA Damage / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019942:Genes, p16; D016158:Genes, p53; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000473:pathology*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016896:Treatment Outcome
C479067:3-aminothioacridone; D000609:Aminoacridines; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D004247:DNA; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases