The potent microtubule-stabilizing agent (+)-discodermolide induces apoptosis in human breast carcinoma cells--preliminary comparisons to paclitaxel.
(+)-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.
Balachandran
R
R
Department of Environmental & Occupational Health, University of Pittsburgh, PA 15238, USA.
ter Haar
E
E
Welsh
M J
MJ
Grant
S G
SG
Day
B W
BW
D000473:Alkanes; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002219:Carbamates; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000187:drug effects; D004171:Diploidy; D005260:Female; D006801:Humans; D007783:Lactones / Q000627:therapeutic use*; D017239:Paclitaxel / Q000627:therapeutic use*; D011753:Pyrones; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000648:ultrastructure
D000473:Alkanes; D000970:Antineoplastic Agents; D002219:Carbamates; D004273:DNA, Neoplasm; D007783:Lactones; D011753:Pyrones; C071229:discodermolide; D017239:Paclitaxel