In accordance with the present invention, there have been identified extracts from a tropical
plant that initiate
paclitaxel-like
microtubule bundling.
Bioassay-directed purification yields the
steroid taccalonolide A. Taccalonolide, like
paclitaxel, initiates the formation of abnormal interphaes and mitotic microtubules. Cells treated with taccalonolide exhibit thick bundles of microtubules that appear to nucleate independent of the
microtubule organizing center. Abnormal mitotic spindles consisting of multi-polar spindles are initiated by taccalonolide and resemble abnormal mitotic spindles found in the presence of
paclitaxel. Like paclitaxel, taccalonolide causes the breakdown of the
nucleus into micronuclei. Taccalonolide causes G2 / M arrest, Bc1-2
phosphorylation and initiates an apoptotic
cascade that includes the activation of
caspase 3. Taccalonolide is an effective inhibitor of proliferation against both SK-OV-3 and MDA-MB-435
cell with IC50 values of 2.3 μM and 2.1 μM respectively. In contrast to paclitaxel, taccalonolide is effective against the multidrug resistant SKVLB-1 cellline and thus appears to be a poor substrate for P-
glycoprotein-mediated transport. Although taccalonolide is almost equipotent with paclitaxel in its effects on cellular microtubules, it is much less potent than paclitaxel in its ability to initiate the
polymerization of purified
tubulin and
microtubule protein. Taccalonolide A is the first microtubule stabilizing agent to be discovered from a
plant since identification of the
mechanism of action of paclitaxel and it is the first
natural product steroid identified to have these cellular effects.