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Dicoumarol: a Unique Microtubule Stabilizing Natural Product That Is Synergistic with Taxol1

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Dicoumarol: a Unique Microtubule Stabilizing Natural Product That Is Synergistic with Taxol1 [CANCER RESEARCH 63, 1214–1220, March 15, 2003] Dicoumarol: A Unique Microtubule Stabilizing Natural Product that Is Synergistic with Taxol1 Hamta Madari, Dulal Panda, Leslie Wilson, and Robert S. Jacobs2 Departments of Ecology, Evolution, and Marine Biology [H. M., R. S. J.] and Molecular, Cellular, and Developmental Biology [L. W.], University of California, Santa Barbara, California 93106, and Bhupat and Jyoti Mehta School of Biosciences and Bioengineering, Indian Institute of Technology, Bombay, Mumbai, India 400076 [D. P.] ABSTRACT prostate cancer, malignant melanoma, and metastatic renal cell carci- noma (12–14). In studies on the antiproliferative actions of coumarin compounds, we In addition, the coumarin anticoagulants, dicoumarol (Dicumarol) -discovered that dicoumarol (a coumarin anticoagulant; 3,3؅-methyl and its synthetic derivative warfarin sodium (Coumadin), have been enebis[4-hydroxycoumarin]) inhibits the first cleavage of Strongylocentro- tus purpuratus (sea urchin) embryos in a concentration-dependent manner shown to decrease metastases in experimental animals (15). Warfarin with 50% inhibition occurring at a concentration of 10 ␮M. Because first sodium, largely replacing dicoumarol therapeutically as an anticoag- cleavage in sea urchin embryos is highly selective for microtubule- ulant, has been used for the treatment of a variety of cancers and targeted agents, we thought that the active compounds might inhibit cell shown to improve tumor response rates and survival in patients with division by interacting with tubulin or microtubules. We found that several types of cancer (16–22). However, despite numerous studies, ␮ dicoumarol binds to bovine brain tubulin with a Kd of 22 M and that 0.1 little information has been acquired on the cellular mechanism of ␮ M dicoumarol strongly stabilizes the growing and shortening dynamics action of coumarin compounds in the treatment of malignancies. at the plus ends of the microtubules in vitro. Dicoumarol reduces the rate Possibly for this reason, the coumarin compounds have not received and extent of shortening, it increases the percentage of time the microtu- bules spend in an attenuated (paused) state, and it reduces the overall much attention for the treatment of cancer. dynamicity of the microtubules. The antimitotic effects of the widely used On further investigation of the coumarin literature, we developed cancer chemotherapeutic agent Taxol (paclitaxel) are also mediated by the hypothesis that coumarin compounds might inhibit cell prolifer- suppressing microtubule dynamics. We demonstrate that exposure to ation by interfering with mitotic spindle microtubule function. Earlier combinations of Taxol and dicoumarol results in a synergistic inhibition of studies revealed that coumarin, 7-hydroxycoumarin, and 4-hydroxy- cell division of sea urchin embryos. The results suggest that the antipro- coumarin inhibit mitosis in Allium cepa root tips (23, 24). Interest- liferative mechanism of action of dicoumarol and possibly related phar- ingly, 7-hydroxycoumarin disorganized the mitotic spindle microtu- macophores may be mediated by tubulin binding and the stabilization of bules in A. cepa cells, leading to the random distribution of the spindle microtubule dynamics. Because of its low toxicity and simple chromosomes at metaphase (24). This is a form of cytotoxicity com- chemical structure, there is potential interest to explore combinations of antimitotic coumarins with other chemotherapeutic agents to improve mon to mitotic spindle poisons that inhibit mitosis by modifying efficacy and lower toxicity. microtubule dynamics (25). Microtubules are intrinsically dynamic polymers composed of the heterodimeric protein tubulin. Both in vitro and in cells, microtubule INTRODUCTION ends switch between growing and shortening states, a behavior termed dynamic instability (see Ref. 25 for a review). Microtubule dynamics Dicoumarol, a natural anticoagulant drug chemically designated as are essential for the proper movements of chromosomes during mi- 3,3Ј-methylenebis[4-hydroxycoumarin], is metabolized from couma- tosis and play a crucial role in passage through the metaphase/ rin in the sweet clover (Melilotus alba and Melilotus officinalis)by anaphase checkpoint. At the onset of mitosis, the interphase microtu- molds, such as Penicillium nigricans and Penicillium jensi. Coumarin bule network is replaced by a population of spindle microtubules that (1,2-benzopyrone), the parent molecule of dicoumarol, is the simplest are 10–100 times more dynamic than the interphase network (26). compound of a large class of naturally occurring phenolic substances These rapid dynamics are crucial for attachment at the kinetochores made of fused benzene and ␣-pyrone rings (1). Our investigation of and proper chromosome alignment for segregation at anaphase (25, coumarin compounds originated when translated Persian literature3 27). Cells with improper spindle assembly or chromosome alignment revealed that a wide spectrum of medicinal plant extracts that were in are prevented from transitioning from metaphase to anaphase by use as early as 1000 A.D. contains a high content of coumarins.4 mitotic checkpoint mechanisms, resulting in cell cycle arrest in mi- Subsequent analysis of scientific literature revealed numerous reports on the antiproliferative and antitumor activities of a variety of cou- tosis followed by apoptosis (28–30). marin compounds, e.g., both coumarin itself and 7-hydroxycoumarin In the present study, we investigated the antimitotic actions of have been reported to inhibit the proliferation of a number of human several coumarin compounds on the first division of sea urchin malignant cell lines in vitro (2–6) and have demonstrated activity embryos. The first few cell divisions of sea urchin embryos exhibit a against several types of animal tumors (7–11). These compounds have remarkable degree of pharmacological selectivity toward mitotic spin- also been reported in clinical trials to demonstrate activity against dle poisons (31). We found that several coumarin compounds inhib- ited the first cleavage of Strongylocentrotus purpuratus embryos in a concentration-dependent manner, the most potent of the coumarins Received 8/12/02; accepted 1/15/03. The costs of publication of this article were defrayed in part by the payment of page tested being dicoumarol. By video microscopy and fluorescence spec- charges. This article must therefore be hereby marked advertisement in accordance with troscopy, we determined that dicoumarol binds to tubulin and sup- 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by Grants 14350100CA31063 and NSI3560 from the United States presses the dynamic instability of individual bovine brain microtu- Department of Interior, Mineral Management Service, and USPHS, respectively. bules in vitro. In addition, we evaluated the combined antiproliferative 2 To whom reprint requests should be addressed, at Department of Ecology, Evolution activity of Taxol (paclitaxel) and dicoumarol in the sea urchin cell and Marine Biology, University of California, Santa Barbara, CA 93106. Phone: (805) 893-4007; Fax: (805) 893-4724; E-mail: [email protected]. division model and found that the combination did produce synergis- 3 Received as a gift from the personal archives of ancient Persian literature of Seyedeh tic inhibition of cell division. In view of the relative simplicity of the Nasrin Sohrab (in memorandum) and translated from the original Farsi by Amin Madari. 4 H. Madari and R. S. Jacobs. Coumarin content of medicinal plant extracts used in coumarin compounds and their microtubule-targeted mechanism of ancient Persian medicines, manuscript in preparation. action, we believe the coumarin pharmacophore may serve as an 1214 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2003 American Association for Cancer Research. DICOUMAROL IS SYNERGISTIC WITH TAXOL important model on which to develop new avenues of cancer chem- achieve three to six seeds per microscope field. After 35 min of incubation, otherapy. samples of microtubule suspensions (2 ␮l) were prepared for video micros- copy, and the dynamic instability behavior of individual microtubules was recorded at 37°C and analyzed as described previously (34). Microtubules MATERIALS AND METHODS were observed for a maximum of 45 min after they had reached steady state. Materials. All drugs and reagents were obtained from Sigma Chemical Co. We considered a microtubule to be in a growth phase if it increased in length Ͼ ␮ Ͼ ␮ (St. Louis, MO) unless otherwise indicated. by 0.2 m at a rate 0.15 m/min and in a shortening phase, if it shortened Ͼ ␮ Ͼ ␮ Inhibition of Cell Cleavage. Sea urchins, either S. purpuratus or Strongy- by 0.2 m at a rate 0.3 m/min. Microtubules undergoing length Յ ␮ locentrotus franciscanus, were induced to spawn by injection of 0.5 M KCl into changes 0.2 m over the duration of six data points were considered to be the coelomic cavity and cultured in filtered seawater, as described previously in an attenuated state. The same tubulin preparation was used for all experi- (31). Eggs were used in fresh filtered seawater at a concentration of ϳ1% ments; 20–30 microtubules were analyzed for each experimental condition. (v/v).5 Sperm were collected directly from the aboral surface of male sea The catastrophe frequency [a catastrophe is a transition from the growing or urchins and diluted into seawater (one drop of concentrated sperm/1 ml of attenuated state to shortening (35)]
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