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

Cell Death Differ. 1998 Dec;5(12):1062-75. doi: 10.1038/sj.cdd.4400436.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Cycle Proteins*
  • Cell Line, Transformed / chemistry
  • Cell Line, Transformed / cytology
  • Cell Line, Transformed / enzymology
  • Chymotrypsin / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclins / antagonists & inhibitors
  • Cyclins / metabolism
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Dimethyl Sulfoxide / pharmacology
  • Dipeptides / metabolism
  • Dipeptides / pharmacology*
  • Etoposide / pharmacology
  • Fibroblasts / chemistry
  • Fibroblasts / cytology
  • Fibroblasts / enzymology
  • Gene Expression Regulation, Viral
  • HL-60 Cells / chemistry
  • HL-60 Cells / cytology
  • HL-60 Cells / enzymology
  • Humans
  • Jurkat Cells / chemistry
  • Jurkat Cells / cytology
  • Jurkat Cells / enzymology
  • Microtubule-Associated Proteins / antagonists & inhibitors
  • Microtubule-Associated Proteins / metabolism*
  • Multienzyme Complexes / metabolism*
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Phthalimides / pharmacology*
  • Poly Adenosine Diphosphate Ribose / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proteasome Endopeptidase Complex
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Simian virus 40 / genetics
  • Solvents / pharmacology
  • Tumor Suppressor Proteins*

Substances

  • Amino Acid Chloromethyl Ketones
  • CDKN1A protein, human
  • CEP 1508
  • CEP 1513
  • CEP 1601
  • Caspase Inhibitors
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Cysteine Proteinase Inhibitors
  • Dipeptides
  • Microtubule-Associated Proteins
  • Multienzyme Complexes
  • N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone
  • Nucleic Acid Synthesis Inhibitors
  • Phthalimides
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Solvents
  • Tumor Suppressor Proteins
  • cyano-(CH2)8CH(cyclopentyl)CO--nitroarginyl-leucine N-ethylketoamide
  • Cyclin-Dependent Kinase Inhibitor p27
  • Poly Adenosine Diphosphate Ribose
  • Etoposide
  • CEP 1612
  • Poly(ADP-ribose) Polymerases
  • Chymotrypsin
  • Caspases
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Dimethyl Sulfoxide