The potent microtubule-stabilizing agent (+)-discodermolide induces apoptosis in human breast carcinoma cells - preliminary comparisons to paclitaxel

被引:54
|
作者
Balachandran, R
ter Haar, E
Welsh, MJ
Grant, SG
Day, BW [1 ]
机构
[1] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15260 USA
[2] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15260 USA
[3] Univ Pittsburgh, Magee Womens Res Inst, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15260 USA
[4] Univ Pittsburgh, Dept Environm & Occupat Hlth, Pittsburgh, PA 15238 USA
关键词
apoptosis; discodermolide; flow cytometry; Hoechst; 33342; paclitaxel; pulsed field gel electrophoresis;
D O I
10.1097/00001813-199801000-00008
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
(+)-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. [(C) 1998 Rapid Science Ltd.].
引用
收藏
页码:67 / 76
页数:10
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