3-amino thioacridone inhibits DNA synthesis and induce DNA damage in T-cell acute lymphoblastic leukemia (T-ALL) in a p16-dependent manner.

Abstract

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

• Authors: Mitchell B Diccianni, John Yu, Gerda Meppelink, Marten de Vries, Lien Shao, Sigrun Gebauer, Hsien Shih, William Roberts, Neil P Kilcoin, Jeanette Pullen, Dennis A Carson, Alice L Yu
• Journal: Journal of experimental therapeutics & oncology (J Exp Ther Oncol) Vol. 4 Issue 3 Pg. 223-37 (Oct 2004) ISSN: 1359-4117 [Print] United States
• PMID: 15724842 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-aminothioacridone
• Aminoacridines
• Enzyme Inhibitors
• Proto-Oncogene Proteins
• DNA
• CDK4 protein, human
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinases

Topics

• Aminoacridines (pharmacology)
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinases (antagonists & inhibitors, pharmacology)
• DNA (biosynthesis)
• DNA Damage (drug effects)
• Enzyme Inhibitors (pharmacology)
• Genes, p16
• Genes, p53
• Humans
• Leukemia-Lymphoma, Adult T-Cell (genetics, pathology)
• Prognosis
• Proto-Oncogene Proteins (antagonists & inhibitors, pharmacology)
• Treatment Outcome