Interactions between 2-fluoroadenine 9-beta-D-arabinofuranoside and the kinase inhibitor UCN-01 in human leukemia and lymphoma cells.

Abstract

Interactions between the purine analogue 2-fluoroadenine 9-beta-D-arabinofuranoside (F-ara-A) and the kinase inhibitor UCN-01 have been examined in human leukemia cells (U937 and HL-60) with respect to induction of mitochondrial damage, caspase activation, apoptosis, and loss of clonogenic survival. Simultaneous or subsequent exposure of F-ara-A-treated cells (2 microM) to UCN-01 (100 nM) resulted in a marked potentiation of apoptosis, manifested by loss of mitochondrial membrane potential (delta psi(m)), cleavage/activation of procaspase-9 and procaspase-3, DNA fragmentation, and degradation of poly-ADP(ribosyl) polymerase. Coadministration of UCN-01 with F-ara-A was also associated with diminished phosphorylation of the cdc25 phosphatase. In contrast, exposure of cells to the sequence UCN-01, followed by F-ara-A, resulted in only a modest increase in apoptotic cells. The ability of UCN-01 to potentiate F-ara-A-mediated lethality was not mimicked by the selective PKC inhibitor bisindolylmaleimide, nor did treatment of cells with UCN-01 enhance formation of F-ara-ATP or increase incorporation of [3H]F-ara-A into DNA. Enhanced apoptosis in cells exposed sequentially or simultaneously to F-ara-A and UCN-01 was accompanied by a substantial reduction in colony formation (e.g., to 0.01% of control values). Cotreatment with UCN-01 also increased F-ara-A-mediated apoptosis and loss of delta psi(m) in U937 cells ectopically expressing Bcl-2, although not to the same extent as that observed in empty-vector controls. Finally, simultaneous exposure (24 h) of malignant B lymphocytes from the pleural effusion of a patient with indolent non-Hodgkin's lymphoma to F-ara-A and UCN-01 ex vivo resulted in a striking increase in apoptosis, as determined by terminal deoxynucleotidyltransferase-mediated nick end labeling assay. These findings indicate that UCN-01 increases F-ara-A-induced mitochondrial damage and apoptosis in human leukemia cells in a sequence-dependent manner, and that these events occur in at least some primary human lymphoma cells.

• Authors: S Harvey, R Decker, Y Dai, G Schaefer, L Tang, L Kramer, P Dent, S Grant
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 7 Issue 2 Pg. 320-30 (Feb 2001) ISSN: 1078-0432 [Print] United States
• PMID: 11234887 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Alkaloids
• Antineoplastic Agents
• Arabinonucleotides
• Enzyme Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• 2-fluoro-araATP
• 7-hydroxystaurosporine
• Protein Kinase C
• Vidarabine
• Staurosporine
• fludarabine

Topics

• Alkaloids (metabolism)
• Antineoplastic Agents (metabolism)
• Apoptosis
• Arabinonucleotides (biosynthesis)
• Blotting, Western
• Drug Interactions
• Drug Synergism
• Enzyme Inhibitors (metabolism)
• HL-60 Cells (cytology, drug effects)
• Humans
• Leukemia (metabolism, pathology)
• Lymphoma (metabolism, pathology)
• Phosphorylation
• Protein Kinase C (antagonists & inhibitors)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Staurosporine (analogs & derivatives)
• U937 Cells (drug effects)
• Vidarabine (analogs & derivatives, metabolism)