(+)-
Discodermolide, a sponge-derived
natural product, stabilizes microtubules more potently than
paclitaxel despite the lack of any obvious structural similarities between the drugs. It competitively inhibits the binding of
paclitaxel to
tubulin polymers, hypernucleates microtubule assembly more potently than
paclitaxel, and inhibits the growth of
paclitaxel-resistant ovarian and colon
carcinoma cells. Because
paclitaxel shows clinical promise for
breast cancer treatment, its effects in a series of human
breast cancer cells were compared to those of (+)-
discodermolide. Growth inhibition, cell and nuclear morphological, and electrophoretic and flow cytometric analyses were performed on (+)-
discodermolide-treated MCF-7 and MDA-MB231 cells. (+)-
Discodermolide potently inhibited the growth of both cell types (IC50 < 2.5 nM) at concentrations similar to those observed with
paclitaxel. Complete inhibition of growth occurred with 10 nM or greater of each
drug and was not reversed by removal. (+)-
Discodermolide-treated cells exhibited condensed and highly fragmented nuclei. Flow cytometric comparison of cells treated with either
drug at 10 nM, a concentration well below that achieved clinically with
paclitaxel, showed both caused cell cycle perturbation and induction of a hypodiploid cell population. (+)-
Discodermolide caused these effects more extensively and at earlier time points. The timing and type of high molecular weight DNA fragmentation induced by the two agents was consistent with induction of apoptosis. The results suggest that (+)-
discodermolide has promise as a new chemotherapeutic agent against breast and other
cancers.