Abstract
It has been suggested that overexpression of the Bcl-2 oncoprotein in human cancer cells contributes to their resistance to apoptosis induced by chemotherapy. We report here that a novel dipeptidyl proteasome inhibitor, CEP1612, at low concentrations rapidly induces apoptosis in human Jurkat T cells overexpressing Bcl-2 and also in all human prostate, breast, tongue and brain tumor cell lines we have tested to date, without exception. In contrast, etoposide, a standard anticancer drug, fails to kill these cells when employed under the same conditions. The apoptosis-inducing abilities of CEP1612 and its analogous compounds match precisely their order for inhibition of the proteasome chymotrypsin-like activity. CEP1612-induced apoptosis is p53-independent, inhibitable by a tetrapeptide caspase inhibitor, and associated with accumulation of the cyclin-dependent kinase inhibitors p21 and p27. Furthermore, CEP1612 selectively accumulates p27 and induces apoptosis in simian virus 40-transformed, but not the parental normal, human fibroblasts. Proteasome inhibitors such as those investigated herein might therefore have potential use as novel anticancer drugs.
Publication types
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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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Apoptosis / drug effects
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Apoptosis / physiology*
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Caspase Inhibitors
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Caspases / metabolism
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Cell Cycle Proteins*
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Cell Line, Transformed / chemistry
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Cell Line, Transformed / cytology
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Cell Line, Transformed / enzymology
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Chymotrypsin / metabolism
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclins / antagonists & inhibitors
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Cyclins / metabolism
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Cysteine Endopeptidases / metabolism*
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Cysteine Proteinase Inhibitors / pharmacology
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Dimethyl Sulfoxide / pharmacology
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Dipeptides / metabolism
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Dipeptides / pharmacology*
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Etoposide / pharmacology
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Fibroblasts / chemistry
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Fibroblasts / cytology
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Fibroblasts / enzymology
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Gene Expression Regulation, Viral
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HL-60 Cells / chemistry
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HL-60 Cells / cytology
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HL-60 Cells / enzymology
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Humans
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Jurkat Cells / chemistry
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Jurkat Cells / cytology
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Jurkat Cells / enzymology
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Microtubule-Associated Proteins / antagonists & inhibitors
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Microtubule-Associated Proteins / metabolism*
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Multienzyme Complexes / metabolism*
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Nucleic Acid Synthesis Inhibitors / pharmacology
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Phthalimides / pharmacology*
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Poly Adenosine Diphosphate Ribose / metabolism
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Poly(ADP-ribose) Polymerase Inhibitors
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Poly(ADP-ribose) Polymerases / metabolism
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Proteasome Endopeptidase Complex
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Simian virus 40 / genetics
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Solvents / pharmacology
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Tumor Suppressor Proteins*
Substances
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Amino Acid Chloromethyl Ketones
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CDKN1A protein, human
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CEP 1508
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CEP 1513
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CEP 1601
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Caspase Inhibitors
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Cysteine Proteinase Inhibitors
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Dipeptides
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Microtubule-Associated Proteins
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Multienzyme Complexes
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N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone
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Nucleic Acid Synthesis Inhibitors
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Phthalimides
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Poly(ADP-ribose) Polymerase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Solvents
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Tumor Suppressor Proteins
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cyano-(CH2)8CH(cyclopentyl)CO--nitroarginyl-leucine N-ethylketoamide
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Cyclin-Dependent Kinase Inhibitor p27
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Poly Adenosine Diphosphate Ribose
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Etoposide
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CEP 1612
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Poly(ADP-ribose) Polymerases
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Chymotrypsin
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Caspases
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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Dimethyl Sulfoxide