Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts.
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.
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Department of Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania, USA.
Goldfarb
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Siman
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D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D002918:Chymotrypsin / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D015967:Gene Expression Regulation, Viral; D018922:HL-60 Cells / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D006801:Humans; D019169:Jurkat Cells / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010797:Phthalimides / Q000494:pharmacology*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013539:Simian virus 40 / Q000235:genetics; D012997:Solvents / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D000590:Amino Acid Chloromethyl Ketones; C493956:CDKN1A protein, human; C118003:CEP 1508; C118074:CEP 1513; C118075:CEP 1601; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D008869:Microtubule-Associated Proteins; D009097:Multienzyme Complexes; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D019384:Nucleic Acid Synthesis Inhibitors; D010797:Phthalimides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D012997:Solvents; D025521:Tumor Suppressor Proteins; C118005:cyano-(CH2)8CH(cyclopentyl)CO--nitroarginyl-leucine N-ethylketoamide; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011064:Poly Adenosine Diphosphate Ribose; D005047:Etoposide; C118004:CEP 1612; D011065:Poly(ADP-ribose) Polymerases; D002918:Chymotrypsin; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D004121:Dimethyl Sulfoxide