Abstract
Cytosine arabinoside (ara-C) is widely used for the treatment of leukemias and displays significant toxicities. Lovastatin, an HMG-CoA reductase inhibitor, is extensively used to treat hypercholesterolemia. To determine whether lovastatin could augment ara-C's activity we have examined their effects in the human erythroleukemia K562 cell line and the ara-C resistant ARAC8D cell line. A synergistic interaction between the two drugs was found. We have demonstrated that the interaction does not occur at the level of RAS but may involve lovastatin's effect of downregulating MAPK activity and preventing ara-C-induced MAPK activation. These studies represent the first description of a potentially beneficial interaction between lovastatin and ara-C that could be applied to the treatment of human leukemia.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / toxicity
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Apoptosis / drug effects
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Cell Division / drug effects
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Cytarabine / administration & dosage
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Cytarabine / pharmacology*
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Cytarabine / toxicity
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Drug Synergism
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / toxicity
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K562 Cells / drug effects*
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K562 Cells / pathology
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Lovastatin / administration & dosage
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Lovastatin / pharmacology*
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Lovastatin / toxicity
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology
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Mitogen-Activated Protein Kinases / metabolism
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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ras Proteins / physiology
Substances
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Cytarabine
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Lovastatin
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Mitogen-Activated Protein Kinases
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ras Proteins