Inhibition of cyclin-dependent kinase activity and induction of apoptosis by preussin in human tumor cells.
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; approximately 500 nM) and to inhibit cell cycle progression into S phase. In agreement with these findings, the level of the cyclin-dependent kinase inhibitor p27(KIP-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 cytochrome c 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.
Achenbach
T V
TV
Institute of Molecular Biology and Tumor Research, Department of Medicine, Philipps University, Marburg, Germany.
Slater
E P
EP
Brummerhop
H
H
Bach
T
T
Müller
R
R
D000841:Anisomycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D003574:Cytochrome c Group / Q000378:metabolism; D003600:Cytosol / Q000737:chemistry; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D019254:Genes, bcl-2 / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D008715:Methionine / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; C058280:preussin; D000841:Anisomycin; D004247:DNA; D008715:Methionine; D018844:Cyclin-Dependent Kinases; D020169:Caspases