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 origina lly 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; similar to 500 nM) and to inhibit cell cycle progression into S phase. In a greement with these findings, the level of the cyclin-dependent kinase inhi bitor p27(KIP-1) is increased in response to preussin treatment while the e xpression of both cyclin A and the transcription factor E2F-1 is down-regul ated. Preussin also induces programmed cell death (apoptosis), which requir es caspase activation and involves the release of cytochrome c from mitocho ndria. 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 th e development of a new class of potent antitumor drugs.