Bulbispermine: A Crinine-Type Amaryllidaceae Alkaloid Exhibiting Cytostatic Activity toward Apoptosis-Resistant Glioma Cells

摘要

The Amaryllidaceae alkdloicl bulbispermine was derivatized to produce a small group of synthetic analogues. These, together with bulbispermine's natural crinine-type congeners, were evaluated in vitro against a panel of cancer cell lines with various levels of resistance to pro-apoptotic stimuli. Bulbispennine, haemanthamine, and haemanthidine showed the most potent antiproliferative activities as determined by the MTT colorimet-ric assay. Among the synthetic bulbispormine analogues, only the C1,C2-dicarbamate derivative exhibited notable growth inhibitory properties. All active compounds were found not to discriminate between the cancer cell lines based on the apop-tosis sensitivity criterion; they displayed similar potencies in both cell types, indicating that the induction of apoptosis is not the primary mechanism responsible for antiproliferative activity in this series of compounds. It was also found that bul-bispermine inhibits the proliferation of glioblastoma cells through cytostatic effects, possibly arising from rigidification of the actin cytoskeleton. These findings lead us to argue that crinine-type alkaloids are potentially useful drug leads for the treatment of apoptosis-resistant cancers and glioblastoma in particular.