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

Abstract

The Amaryllidaceae alkaloid 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 proapoptotic stimuli. Bulbispermine, haemanthamine and haemanthidine showed the most potent antiproliferative activities as determined by the MTT colorimetric assay. Among the synthetic bulbispermine analogues, only the C1,C2-dicarbamate derivative exhibited noteworthy growth inhibitory properties. All active compounds were found not to discriminate between the cancer cell lines based on the apoptosis sensitivity criterion and displayed comparable potencies in both cell types, indicating that apoptosis induction is not the primary mechanism responsible for antiproliferative activity in this series of compounds. It was also found that bulbispermine inhibits the proliferation of glioblastoma cells through cytostatic effects, possibly arising from the 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.

Activity of 2-Aryl-2-(3-indolyl)acetohydroxamates against Drug-Resistant Cancer Cells

“…To obtain insight into the effectiveness of 2-aryl-2-(3-indolyl)acetohydroxamates against apoptosis-resistant cancers, computer-assisted phase-contrast microscopy 12,13,15 (quantitative videomicroscopy) was employed to observe the phenotypic morphological changes in cancer cells as they are treated with these compounds. Figure 4 shows that acetohydroxamate 3aafa inhibits cancer cell proliferation without inducing cell death when assayed at concentrations slightly exceeding the GI 50 values (25 μM) in SKMEL-28 melanoma and U373 glioblastoma cells, both exhibiting resistance to various proapoptotic stimuli.…”

“…5,9,10 One solution to apoptosis resistance entails the complementation of cytotoxic therapeutic regimens with cytostatic agents and thus a search for novel cytostatic anticancer drugs that can overcome cancer cell resistance to apoptosis is an important pursuit. 12–15 …”

Jonquailine, a new pretazettine-type alkaloid isolated from Narcissus jonquilla quail, with activity against drug-resistant cancer

“…Resistance to apoptosis, and thus to conventional chemotherapy, is also an intrinsic property of tumor metastases, which remains an important clinical challenge as 90% of cancer patients die from metastastic cancer [6,7]. An important solution to chemotherapy resistance entails the complementation of cytotoxic therapeutic regimens with cytostatic agents [8–11], which can often sensitize cancer cells to apoptosis and thus display synergistic effects, making the search for such agents an important pursuit [12–15]. …”

“…1). These have attracted considerable attention, most prominently because of their activity against drug-resistant cancers with dismal prognoses, which is most likely due to their cytostatic non-apoptotic antiproliferative mechanisms [8–11,28]. Among other possible effects contributing to cytostaticity, the inhibition of eukaryotic protein synthesis by these natural products apparently plays a major role in their anticancer action [23,29,30].…”

Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines

“…In the related publication [55], we show that these observations also apply to α,β-unsaturated 1,4-dialdehyde terpenoids, such as 1 and 9-epipolygodial, and that cancer cell death induced by these compounds cannot be explained by TRPV1-targeting. In an effort to gain insight into possible mechanisms associated with antiproliferative properties of 1 and the C12-Wittig derivatives, the morphological changes in cells treated with these compounds were studied with computer-assisted phase-contrast microscopy [14] (quantitative videomicroscopy). Figure 8 shows that 1 , at a concentration equalling its GI 50 value against the U373 cell line (Table 1), exhibited strong fixative effects on these GBM cells.…”