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Estramustine Depolymerizes Microtnbules by Binding to Tubulin 1

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Estramustine Depolymerizes Microtnbules by Binding to Tubulin 1 [CANCER RESEARCH 53, 4573-4581, October 1, 1993] Estramustine Depolymerizes Microtnbules by Binding to Tubulin 1 Bjfrn Dahll6f, 2 Anita Bilistr6m, Fernando Cabral, and Beryl Hartley-Asp Kabi Pharmacia Oncology, S-223 63 Lund, Sweden lB. D., A. B., B. HA.], and Department of Pharmacology, University of Texas Medical School, Houston, Texas 77225 [F. C.] ABSTRACT Experiments using purified microtubule proteins from rat brain and from DU 145 human prostate cancer cells suggested that the antimi- To investigate the mechanism of action of the antineoplastic drug es- totic effects of estramustine were caused by binding of the drug to tramustine, we compared its effects on human prostate cancer cells with those of vinblastine. At their respective concentrations that result in 50% MAPs (9, 10). Such an interaction, revealed by binding of radiola- inhibition of clonogenic growth, both drugs caused an accumulation of beled EM to MAPs and by the ability of EM to strip MAPs from cells blocked at mitosis and similar dose- and time-dependent depolymer- taxol-stabilized microtubules in vitro, was believed to lead to disas- ization of interphase microtubules. Also, coicemid-resistant and colcemid- sembly of microtubules. However, it should be noted that these au- hypersensitive Chinese hamster ovary cells with tubulin mutations were thors also showed binding of EM to tubulin but interpreted this as collaterally cross-resistant or -sensitive to estramustine. Thus, the cyto- being nonspecific. Investigators (11) from another laboratory also toxicity of estramustine is due to its microtubule depolymerization prop- reported binding of EM to both tubulin and MAPs but could not detect erties. This could be caused by interaction with tubulin and/or with mi- any depolymerizing activity of EM in vitro. Thus, the actual target for crotubule-associated proteins (MAPs). Previous investigations have shown the antimicrotubule activity of EM has not yet been unequivocally that high concentrations of estramustine phosphate can inhibit microtu- bule polymerization in vitro by binding to MAPs. However, estramustine determined. phosphate is the clinical prodrug to estramustine, the intracellular active Curiously, it was found that the prodrug EMP also possessed anti- compound. In this study, we investigated the effects of estramustine on the microtubule activity, but only in microtubule polymerization experi- binding of MAPs to taxoi-stabilized microtubulesin vivo. In contrast to ments in vitro (12, 13). In experiments using cultured cells, EMP previous reports, no effect of estramustine on the binding of MAPs to either is inactive because it cannot penetrate the plasma membrane microtubules was found. Furthermore, we found that polymerization of (see "Results") or demonstrates activity identical with that of EM. The purified tubulin could be inhibited by estramustine in vitro. Taken to- latter result was found in glioma cells and was shown to be due to gether, these results demonstrate that estramnstine causes depolymeriza- dephosphorylation of EMP by cellular phosphatases (14). The micro- tion of microtubules by direct interaction with tubulin. tubule-depolymerizing activity of EMP in vitro was shown to be due to interactions between the negatively charged estramustine phosphate INTRODUCTION molecule with the positively charged tubulin-binding domains of EM 3 is an antineoplastic drug used in the treatment of advanced MAPs (15, 16). It is important to remember that this interaction is prostate cancer. The active compound consists of a 17/3-estradiol purely an in vitro phenomenon which is irrelevant for the intracellular group linked to nitrogen mustard via a carbamate bridge (Fig. 1). mode of action of EM. Unfortunately, in the vast majority of the Clinically, EM is given as the prodrug EMP, which is subsequently literature concerning EM, the proper distinction between the modes of dephosphorylated when administered both p.o. and i.v. (1). action of EM and EMP has not been made. EM was designed to function as an alkylating drug targeted to In order to study the mechanism of action of EM, we have com- estrogen receptor-bearing cells (e.g., breast cancer cells). There, the pared the cytotoxic and antimicrotubule effects of EM with those of carbamate bridge would be cleaved to release nor-nitrogen mustard. VLB, a well-characterized antimitotic drug with affinity for tubulin, However, the compound was found to be devoid of alkylating activity which recently has been combined with EM for the treatment of due to unanticipated stability of the carbamate bridge and lack of advanced prostate cancer (17, 18). Our results show that the two drugs alkylating activity of the intact molecule (2, 3). Also, the intact estra- are qualitatively similar with respect to cellular effects, which sug- mustine molecule did not show any significant binding to estrogen gests a common mode of action. This prompted us to carry out further receptors (3, 4). For a review of these properties of EM, see Ref. 5. experiments to challenge the hypothesis that EM exerts its action via Although EM did not exhibit the predicted properties for which the binding to MAPs. Evidence is presented which shows that EM, both drug was developed, the intact molecule had pronounced cytotoxicity in vivo (cell culture) and in vitro, causes microtubule disassembly by independent of any hormonal or alkylating activities (3, 5, 6). It was interaction with tubulin. shown that EM belongs to the group of antimitotic drugs, such as the Vinca alkaloids and colchicine, which can disrupt the microtubule MATERIALS AND METHODS network of cells in tissue culture and block cells at mitosis (7). Also, EM has recently been shown to block cells at mitosis in prostate tumor Cell Culture. The DU 145 cell line (purchased from American Type Cul- xenografts (8). ture Collection) was derived from a metastatic brain lesion of a human prostate adenocarcinoma and cultured as previously described (6). Growth conditions and characteristics of the CHO cell lines have previously been described (19). Received 3/8/93; accepted 7/19/93. Drugs. EM (estradiol-3-N-bis(2-chloroethyl)carbamate) and EMP were The costs of publication of this article were defrayed in part by the payment of page synthesized by Kabi Pharmacia (Lund, Sweden). VLB was purchased from charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Lilly, and taxol was from Sigma or as a gift to F. C. from Dr. Matthew Suffness 1 This work was funded in part by Grant CA52962 from the National Institutes of of the National Cancer Institute. For each experiment, fresh stock solutions Health to E C. were made in DMSO and diluted in medium to a final concentration of 0.1% 2 To whom requests for reprints should be addressed, at Departmentof Cell Biology, DMSO. Kabi Pharmacia Oncology,Scheelevagen 22, S-223 63 Lund, Sweden. 3 The abbreviations used are: EM, estramustine; BSA, bovine serum albumin; CHO, Antibodies. Mouse anti-/3-tubulin (N357) was purchased from Amersham; Chinese hamster ovary; DMSO, dimethylsulfoxide; EMP, estramustinephosphate; IC5o, alkaline phosphatase-conjugated rabbit anti-mouse antibody ($3721) was from concentration which results in 50% inhibitionof clonogenicgrowth; MAP, microtubule- Promega; fluorescein isothiocyanate-conjugated goat anti-mouse antibody associated protein; MTP, microtubuleproteins; PBS, phosphate-bufferedsaline; PC-tubu- (F479), and tetramethylrhodamine B isothiocyanate-conjugated swine anti- lin, phosphocellulose-purifiedtubulin; Pipes, 1,4-piperazinediethanesulfonicacid; SDS, sodium dodecylsulfate; PAGE, polyacrylamidegel electrophoresis;TBST, Tris-buffered rabbit antibody (R156) were from from Dako A/S, Denmark. Rabbit antiserum saline + Tween 20; VLB, vinblastine. recognizing CHO-MAPs was raised against a heat-stable protein (Mr 210,000) 4573 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1993 American Association for Cancer Research. MODE OF ACTION OF ESTRAMUST1NE OR (4% SDS-30% sucrose-10 mM dithiothreitoi-100 mM Tris-HC1, pH 6.8-0.01% bromophenol blue) and then combined with cytoskeletal pellets suspended in nor-nitrogen mustard 20 p,1 of water. To verify that the method resulted in identical amounts of protein in corresponding fractions from different wells, the cells were labeled CICH2CH2. ~ with [35S]methionine prior to treatment with drug, and protein in each fraction CICH2CH2~ N-C-O was quantitated by liquid scintillation counting (data not shown). Protein Electrophoresis and Immunodetection. The cytoskeletal frac- R = H; estrarnustine tions were taken through two rounds of freezing and thawing in order to reduce R = phosphate; estramustine phosphate the viscosity caused by high molecular weight DNA. An equal volume of both Fig. 1. Chemical structure of estramustine and estramustine phosphate. Nor-nitrogen fractions were mixed with the same volume of SDS-PAGE sample buffer and mustard has been linked via a carbamate bridge to estradiol (see "Introduction"). heated to 95~ for 5 min. The samples were alkylated by the addition of a 0.1 volume of 0.5 M iodoacetamide and incubated for 10 min at room temperature. SDS-PAGE was run in a Protean II xi cell (length, 20 cm; Bio-Rad) using a standard buffer system and 14% homogeneous gels, T = 0.37%, at 10 mA of 100 EM constant current overnight without cooling. Each lane contained 40 ~1 of sample. Rainbow molecular weight markers from Amersham (United King- 80 \ dom) were used for determination
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