Abstract
Aminopeptidase enzyme inhibition is thought to deplete the free intracellular amino acids needed by malignant cells for growth and development, resulting in profound anti-proliferative and apoptotic effects. In this study, we investigated the effects of the metalloenzyme-inhibitor CHR-2797 (tosedostat), in primary acute myeloid leukemia (AML) cells. CHR-2797 demonstrated marked in vitro cytotoxicity in AML samples and strong synergy with Cytarabine (Ara-C), but significantly less cytotoxicity to normal marrow progenitors. Furthermore mechanistic investigations revealed that CHR-2797 inhibited the intrinsic nuclear, cytoplasmic and cell surface aminopeptidase function of AML blasts in a dose-dependent manner, demonstrating a promising novel approach for AML therapy.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
-
Adult
-
Aminopeptidases / antagonists & inhibitors*
-
Antineoplastic Agents / administration & dosage
-
Antineoplastic Agents / pharmacology
-
Antineoplastic Agents / therapeutic use
-
Antineoplastic Combined Chemotherapy Protocols / pharmacology
-
Cell Culture Techniques
-
Cytarabine / administration & dosage
-
Cytarabine / pharmacology
-
Drug Evaluation, Preclinical
-
Enzyme Inhibitors / pharmacology
-
Enzyme Inhibitors / therapeutic use
-
Female
-
Glycine / analogs & derivatives*
-
Glycine / pharmacology
-
Glycine / therapeutic use
-
Humans
-
Hydroxamic Acids / pharmacology*
-
Hydroxamic Acids / therapeutic use*
-
Leukemia, Myeloid, Acute / drug therapy*
-
Leukemia, Myeloid, Acute / enzymology
-
Leukemia, Myeloid, Acute / pathology
-
Male
-
Middle Aged
-
Tumor Cells, Cultured
-
Young Adult
Substances
-
Antineoplastic Agents
-
CHR-79888
-
Enzyme Inhibitors
-
Hydroxamic Acids
-
Cytarabine
-
Aminopeptidases
-
tosedostat
-
Glycine