Abstract
Proteasome inhibition has emerged as a novel approach to anticancer therapy. Numerous natural compounds, such as gambogic acid, have been tested in vitro and in vivo as anticancer agents for cancer prevention and therapy. However, whether gambogic acid has chemosensitizing properties when combined with proteasome inhibitors in the treatment of malignant cells is still unknown. In an effort to investigate this effect, human leukemia K562 cells, mouse hepatocarcinoma H22 cells and H22 cell allografts were treated with gambogic acid, a proteasome inhibitor (MG132 or MG262) or the combination of both, followed by measurement of cellular viability, apoptosis induction and tumor growth inhibition. We report, for the first time, that: (i) the combination of natural product gambogic acid and the proteasome inhibitor MG132 or MG262 results in a synergistic inhibitory effect on growth of malignant cells and tumors in allograft animal models and (ii) there was no apparent systemic toxicity observed in the animals treated with the combination. Therefore, the findings presented in this study demonstrate that natural product gambogic acid is a valuable candidate to be used in combination with proteasome inhibitors, thus representing a compelling anticancer strategy.
Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Animals
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Apoptosis / drug effects
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Blotting, Western
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Boronic Acids / administration & dosage
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Boronic Acids / pharmacology
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Caspase Inhibitors
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Caspases / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Cycloheximide / pharmacology
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Cysteine Proteinase Inhibitors / administration & dosage
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Cysteine Proteinase Inhibitors / pharmacology*
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Drug Synergism
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Humans
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K562 Cells
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Leupeptins / administration & dosage
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Leupeptins / pharmacology
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Male
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Mice
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Neoplasms, Experimental / drug therapy*
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Proteasome Endopeptidase Complex / metabolism
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Proteasome Inhibitors
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Protein Synthesis Inhibitors / pharmacology
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Signal Transduction / drug effects
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Transplantation, Homologous
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Tumor Burden / drug effects
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Xanthones / administration & dosage
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Xanthones / pharmacology*
Substances
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Amino Acid Chloromethyl Ketones
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Boronic Acids
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors
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Leupeptins
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MG 262
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Proteasome Inhibitors
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Protein Synthesis Inhibitors
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Xanthones
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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gambogic acid
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Cycloheximide
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Caspases
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde