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Suppression of Microtubule Dynamics by Discodermolide by a Novel Mechanism Is Associated with Mitotic Arrest and Inhibition of Tumor Cell Proliferation

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Suppression of Microtubule Dynamics by Discodermolide by a Novel Mechanism Is Associated with Mitotic Arrest and Inhibition of Tumor Cell Proliferation Molecular Cancer Therapeutics 1303 Suppression of microtubule dynamics by discodermolide by a novel mechanism is associated with mitotic arrest and inhibition of tumor cell proliferation Ste´phane Honore,1 Kathy Kamath,2 Diane Braguer,1 tubule dynamics as compared with those of paclitaxel that Leslie Wilson,2 Claudette Briand,1 and may in turn reflect differences in their binding sites and Mary Ann Jordan2 their effects on tubulin conformation. (Mol Cancer Ther. 2003;2(12):1303–1311) 1 UMR-CNRS 6032, Universite´ de la Me´diterrane´e, Marseille, France and 2 Department of Molecular, Cellular and Developmen- tal Biology and Neuroscience Research Institute, University of Introduction California, Santa Barbara, CA Microtubule-targeted drugs, including the taxanes and Vinca alkaloids, are powerful chemotherapeutic agents Abstract used for treatment of many types of human tumors. However, the problem of the development of clinical Discodermolide is a new microtubule-targeted drug in resistance to taxanes and Vinca alkaloids, as well as the Phase I clinical trials that inhibits tumor growth and general clinical success of microtubules as a target for induces G2-M cell cycle arrest. It is effective against anticancer drugs, have highlighted the need for new paclitaxel-resistant cell lines and acts synergistically in microtubule-targeted chemotherapeutic drugs. Discoder- combination with paclitaxel. Suppression of microtubule molide (Fig. 1) is a new and structurally unique dynamics by microtubule-targeted drugs has been hypoth- compound isolated from a marine sponge, Discodermia esized to be responsible for their ability to inhibit mitotic dissoluta. It was first described as an immunosuppressive progression and cell proliferation. To determine whether agent (1) but more recently, it has been found to enhance discodermolide blocks mitosis by an effect on microtubule the nucleation of microtubules and their stability to dynamics, we analyzed the effects of discodermolide depolymerization by cold temperature or Ca2+ more on microtubule dynamics in living A549 human lung potently than paclitaxel (2). The drug is particularly cancer cells during interphase at concentrations that interesting because it is effective against paclitaxel- block mitosis and inhibit cell proliferation. We found resistant cell lines and acts synergistically in combination that discodermolide (7–166 nM) significantly suppressed with paclitaxel (2, 3). In the hollow fiber mouse model, microtubule dynamic instability. At the IC50 for prolifera- discodermolide produced significant inhibition at tolerat- tion (7 nM discodermolide, 72 h), overall dynamicity was ed doses against a panel of human tumor cells, including reduced by 23%. The principal parameters of dynamic paclitaxel-resistant tumor cells. In human tumor xenograft instability suppressed by discodermolide were the micro- models, it is efficacious at tolerated doses against non- tubule shortening rate and length shortened. In addition, small cell lung, breast, and colon tumor models, some of discodermolide markedly increased the frequency of which are refractory to paclitaxel. Growth inhibitory rescued catastrophes. At the discodermolide concentra- activity is dose dependent and sustained for 5 weeks (or tion that resulted in 50% of maximal mitotic block (83 nM, more) after administration of a single i.v. bolus dose of 20 h), most microtubules were completely non-dynamic, 15 mg/kg (4, 5). It is currently in Phase I clinical trials (6). no anaphases occurred, and all spindles were abnormal. Discodermolide induces microtubule bundling at high The dynamicity of the remaining dynamic microtubules concentrations, cell cycle arrest in the G -M phase, was reduced by 62%. The results indicate that a principal 2 aneuploidy, and apoptosis (7–9). It competitively and very mechanism of inhibition of cell proliferation and mitotic strongly inhibits the binding of paclitaxel to microtubules, block by discodermolide is suppression of microtubule suggesting that the two drugs may have common or dynamics. Importantly, the results indicate significant overlapping binding sites (2, 10), although it remains additional stabilizing effects of discodermolide on micro- possible that discodermolide binds to more than one site on microtubules. The finding that discodermolide cannot substitute for paclitaxel in paclitaxel-requiring cells, where- Received 8/5/03; revised 9/26/03; accepted 10/7/03. as another microtubule-stabilizing drug, epothilone B, can The costs of publication of this article were defrayed in part by the substitute for paclitaxel (3), suggests that there are payment of page charges. This article must therefore be hereby significant differences between the mechanisms of disco- marked advertisement in accordance with 18 U.S.C. Section 1734 dermolide, paclitaxel, and epothilones. solely to indicate this fact. Grant support: GEFLUC Marseille Provence, by the Association pour la Inhibition of microtubule dynamics is a fundamental Recherche sur le Cancer (ARC), from whom S. H. received a fellowship, mechanism of action of several microtubule-targeted and by NIH CA57291 and NS13560. drugs (11, 12). One form of microtubule dynamics, called Requests for Reprints: Mary Ann Jordan, Department of Molecular, dynamic instability, is a behavior in which the ends of Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106. Phone: (805) 893-5317; Fax: (805) 893-4724. microtubules undergo frequent stochastic transitions E-mail: [email protected] between episodes of growing and shortening. Dynamic Downloaded from mct.aacrjournals.org on September 24, 2021. © 2003 American Association for Cancer Research. 1304 Mechanism of Action of Discodermolide 96-well microtiter plates and allowed to attach for 24 h. After incubation with the indicated drug concentrations for 72 h, cell proliferation was determined using the sulforhod- amine B assay (19). Fluorescence Microscopy After growth for 24 h in Labtek II chambers (Nalge Nunc, Rochester, NY), A549 cells were incubated with discoder- Figure 1. Structure of (+)-discodermolide. molide at the indicated concentrations for 20 h. Immuno- fluorescence microscopy of microtubules and DNA staining were performed as previously described (20). instability appears to be essential for progression through Briefly, cells were fixed with 3.7% formaldehyde in PBS mitosis. Suppression of microtubule dynamic instability and stained with an anti-tubulin antibody, tetramethyl by microtubule-targeted drugs is associated with aberrant rhodamine isothiocyanate (TRITC)-conjugated secondary organization of mitotic spindles and inhibition of progress antibody and 4V,6-diamidino-2-phenylindole (DAPI) (Sig- into anaphase (13–17). We recently found that microtu- ma, St. Louis, MO). bule dynamics must be finely regulated for progress Preparation and Microinjection of Rhodamine- through mitosis, and that both excessively rapid dynamics Labeled Tubulin as well as suppressed dynamics correlate with impaired mitotic spindle function and inhibition of cell proliferation Rhodamine-labeled tubulin was prepared using carbox- (18). Information on the effects of discodermolide on ymethylrhodamine (Molecular Probes, Eugene, OR) labeling microtubule dynamics in vitro or in cells is lacking. of microtubules assembled from phosphocellulose-purified Whether, and if so, how, discodermolide blocks mitosis bovine brain tubulin (18). Labeled tubulin was stored in 6-Al aliquots at À70jC until use. A549 cells were seeded and inhibits cell proliferation by an effect on microtubule 5 dynamics has not been determined. 48 h before use at 0.5  10 cells/ml on glass coverslips A A Inthepresentwork,weanalyzedtheeffectsof coated with 10 g/ml laminin and 20 g/ml fibronectin discodermolide on the dynamic instability of individual (Life Technologies, Inc., Carlsbad, CA). Rhodamine-tubu- microtubules in living human A549 lung cancer cells. We lin (5 mg/ml) was centrifuged in a Beckman (Palo Alto, found that discodermolide strongly suppresses microtu- CA) tabletop ultracentrifuge using a TLA 100.3 rotor at  j bule dynamic instability in a concentration-dependent 38,000 g for 14 min at 4 C to remove aggregates just manner. At the concentration of discodermolide that before microinjecting into A549 cells using a Transjector 5246 and Injectman (Eppendorf AG, Hamburg, Germany). inhibits cell proliferation by 50% at 72 h (7 nM), overall j dynamicity was reduced by 23%. The principal parameters Injected cells were incubated for 2 h at 37 C to allow for of dynamic instability that were altered include a decrease incorporation of rhodamine-tubulin into microtubules and in the mean shortening rate and length together with an further incubated with discodermolide for 4 h to allow increase in the rescue frequency. When the concentration of attainment of an equilibrium intracellular drug concen- discodermolide was increased to the concentration that tration. Time-Lapse Microscopy and Image Acquisition blocked mitosis by 50% (83 nM), dynamicity was reduced by 62%, and most of the dynamic instability parameters Microinjected cells were placed in RPMI culture medium were significantly affected. There are significant differences lacking sodium bicarbonate and supplemented with 25 mM between the effects of discodermolide, epothilone B, and HEPES, 4.5 g/l glucose, and 30 Al Oxyrase/ml (Oxyrase paclitaxel on microtubule dynamics that may reflect Inc., Mansfield, OH) to reduce photodamage, in a double differences in their binding sites
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