Open AccessInhibition of Cyclin-Dependent Kinase Activity and Induction of Apoptosis by Preussin in Human Tumor Cells
Author(s) -
Tatjana V. Achenbach,
Emily P. Slater,
Harm Brummerhop,
Thorsten Bach,
Rolf Müller
Publication year - 2000
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.44.10.2794-2801.2000
Subject(s) - apoptosis , cyclin dependent kinase , cyclin a , cell cycle , kinase , biology , cyclin d , cyclin e , cyclin , cell cycle checkpoint , programmed cell death , cyclin dependent kinase 2 , growth inhibition , cancer research , microbiology and biotechnology , biochemistry
In this paper, we report that (+)-preussin, a pyrrolidinol alkaloid originally identified as an antifungal agent, has growth-inhibitory and cytotoxic effects on human cancer cells. Preussin was found to be a potent inhibitor of cyclin E kinase (CDK2-cyclin E) in vitro (50% inhibitory concentration; ∼500 nM) and to inhibit cell cycle progression into S phase. In agreement with these findings, the level of the cyclin-dependent kinase inhibitor p27KIP-1 is increased in response to preussin treatment while the expression of both cyclin A and the transcription factor E2F-1 is down-regulated. Preussin also induces programmed cell death (apoptosis), which requires caspase activation and involves the release of cytochromec from mitochondria. This induction of apoptosis is not blocked by high levels of Bcl-2, which usually confers resistance to chemotherapeutic agents. Taken together, our data indicate that preussin could be a promising lead compound for the development of a new class of potent antitumor drugs.