CEP1612, a dipeptidyl proteasome inhibitor, induces p27WAF1and p27KIP1expression and apoptosis and inhibits the growth of the human lung adenocarcinoma A-549 in nude mice

Jiazhi Sun, Sangkil Nam, Chang Sun Lee, Benyi Li, Domenico Coppola, Andrew D. Hamilton, Q. Ping Dou, Saïd M. Sebti

Research output: Contribution to journalArticlepeer-review

Abstract

The ubiquitin proteasome system is responsible for the proteolysis of important cell cycle and apoptosis-regulatory proteins. In this paper we report that the dipeptidyl proteasome inhibitor, phthalimide- (CH2)8CH-(cyclopentyl) CO-Arg(NO2)-Leu-H (CEP1612), induces apoptosis and inhibits tumor growth of the human lung cancer cell line A-549 in an in vivo model. In cultured A-549 cells, CEP1612 treatment results in accumulation of two proteasome natural substrates, the cyclin-dependent kinase inhibitors p21WAF1and p27KIP1indicating its ability to inhibit proteasome activity in intact cells. Furthermore, CEP1612 induces apoptosis as evident by caspase-3 activation and poly(ADP-ribose) polymerase cleavage. Treatment of A-549 tumor-bearing nude mice with CEP1612 (10 mg/kg/day, i.p. for 31 days) resulted in massive induction of apoptosis and significant (68%; P < 0.05) tumor growth inhibition, as shown by terminal deoxynucleotidyltransferase-mediated UTP end labeling. Furthermore, immunostaining of tumor specimens demonstrated in vivo accumulation of p21WAF1and p27KIP1after CEP1612 treatment. The results suggest that CEP1612 is a promising candidate for further development as an anticancer drug and demonstrate the feasibility of using proteasome inhibitors as novel antitumor agents.

Original languageEnglish (US)
Pages (from-to)1280-1284
Number of pages5
JournalCancer Research
Volume61
Issue number4
StatePublished - Feb 15 2001

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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