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Endocrine-Related Cancer 14 (3) 839 -845     DOI: 10.1677/ERC-07-0096
Copyright © 2007 by the Society for Endocrinology
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Valproic acid enhances tubulin acetylation and apoptotic activity of paclitaxel on anaplastic thyroid cancer cell lines

 Maria G Catalano1, Roberta Poli2, Mariateresa Pugliese2, Nicoletta Fortunati2 and Giuseppe Boccuzzi1,2

1 Department of Clinical Pathophysiology, University of Turin, Via Genova, 3, 10126 Turin, Italy
2 Oncological Endocrinology, ASO San Giovanni Battista, C.so Bramante 88, 10126 Turin, Italy

(Correspondence should be addressed to G Boccuzzi; Email: giuseppe.boccuzzi{at}unito.it)


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
The introduction of paclitaxel into multimodal therapy for anaplastic thyroid carcinoma has failed to improve overall survival. Toxicity rules out the high doses required, especially in older patients. The search for strategies to enhance paclitaxel antineoplastic activity and reduce its side effects is thus advisable. The study aimed to determine whether the histone deacetylase (HDAC) inhibitor valproic acid (VPA) improves the anticancer action of paclitaxel and elucidate the mechanisms underlying the effects of combined treatment. We examined the effect of VPA on the sensitivity to paclitaxel of two anaplastic thyroid carcinoma cell lines (CAL-62 and ARO), and the ability of the drug to determine tubulin acetylation and enhance paclitaxel-induced acetylation. The addition of as little as 0.7 mM VPA to paclitaxel enhances both cytostatic and cytotoxic effects of paclitaxel alone. Increased apoptosis explains the enhancement of the cytotoxic effect. The mechanism underlying this effect is through inhibition of HDAC6 activity, which leads to tubulin hyperacetylation. The results suggest a mechanistic link between HDAC6 inhibition, tubulin acetylation, and the VPA-induced enhancement of paclitaxel effects, and provide the rationale for designing future combination therapies.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Anaplastic thyroid cancer (ATC) is one of the most lethal malignancies, with a rapidly fatal clinical course (Pasieka 2003). Management of ATC has not yet been standardized; multimodal treatments including surgical resection associated with radiotherapy and combination chemotherapy are currently used (Kebebew et al. 2005), but efforts to improve survival have been disappointed (Brignardello et al. 2007).

The introduction of paclitaxel, which had been reported to produce a response rate of about 50% (Ain et al. 2000), has not modified overall survival, because neurological and hematological side effects limit the use of this drug, especially in older patients; incidence and severity of toxicity appear to be related to both peak concentration and total duration of treatment (Markman 2003). Paclitaxel is a microtubule-targeting drug, and it is now recognized that binding the drug to microtubules, by powerfully stabilizing their dynamics without increasing the polymerization mass, is sufficient to lead to mitotic arrest and apoptosis (Jordan et al. 1996). Indeed, all stages of mitosis require highly dynamic microtubules in the spindle, ensuring timely and precise chromosome movement. Strategies or drugs that enhance paclitaxel effect on microtubule stability might improve the drug antineoplastic activity, reducing the incidence of the severe side effects associated with the use of high doses. Indeed, the identification of drugs able to increase antitumoral effects of paclitaxel is now under investigation (Yeung et al. 2000, Vivat-Hannah et al. 2001, Copland et al. 2006).

Histone deacetylase inhibitors (HDI) are a class of potent antineoplastic agents that induce differentiation, growth arrest, and apoptosis of transformed cells (Marks et al. 2001, Vigushin & Coombes 2002, Rosato & Grant 2003). Moreover, reinforcement of the killing activity of drugs targeting DNA has recently been reported (Marchion et al. 2004, 2005, Catalano et al. 2006) for HDI, but the mechanism underlying this effect is poorly understood. Besides, histones and other nonhistone proteins such as transcription factors p53, E2FI, and {alpha}-Jun, {alpha}-tubulin is also a substrate of histone deacetylases (HDACs; Zhang et al. 2003). Notably, it has been demonstrated that the state of tubulin acetylation is linked to microtubule dynamics and has a role in regulating microtubule stability (Matsuyama et al. 2002).

The aim of this work is to explore whether valproic acid (VPA), a widely used anticonvulsant drug which is a class I/II HDI (Gottlicher et al. 2001, Phiel et al. 2001), by inhibiting tubulin deacetylation, might enhance the effects of microtubule-targeting drugs. We report elsewhere that, at concentrations reached in the serum of patients treated for epilepsy, VPA promotes iodine uptake (Fortunati et al. 2004) and controls cell growth (Catalano et al. 2005) in poorly differentiated thyroid cancer cells. Here, we show that, in ATC cell lines, VPA clearly enhances paclitaxel effect on cell viability and apoptosis, by regulating the tubulin acetylation state.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Cell lines and culture conditions

Anaplastic thyroid carcinoma (CAL-62) cell line was purchased from Deutche Sammlung von Mikroorganismen and Zellculturen (Braunschweig, Germany). Anaplastic thyroid carcinoma (ARO) cells were a kind gift from Prof. Paola Cassoni (Pathology Service, Department of Oncology, University of Turin, Turin, Italy). CAL-62 cells were routinely maintained in 25 cm2 flasks at 37 °C, in 5% CO2 and 95% humidity, with 100 IU/ml penicillin and 100 µg/ml streptomycin added, in DMEM-F12 (Invitrogen) supplemented with 10% heat-inactivated FCS (fetal calf serum; Euro-clone, Wetherby, West York, UK). ARO cell line was maintained in RPMI 1640 (Sigma) supplemented with 10% heat-inactivated FCS.

Antitumor activity

To evaluate the effect of VPA on paclitaxel antitumor activity, CAL-62 and ARO cells were seeded at 1 x 103 cells/well in 96-well plates (Corning, New York, NY, USA) in culture medium plus 10% heat-inactivated FCS (Sigma). After 48 h, cells were exposed to 0.7 mM VPA for 24 h before the addition of paclitaxel (0.001–1 µM). After a further 72-h incubation, cell viability was assessed using the Cell Proliferation Reagent WST-1 (Roche Applied Science), following the manufacturer’s instructions. Four replicate wells were used to determine each data point. Three response parameters, median growth inhibition (GI50), total GI (TGI), and median lethal concentration (LC50), were calculated for each cell line. The GI50 corresponds to the concentration of the compound that inhibits 50% net cell growth; the TGI value is concentration of the compound leading to total inhibition; and the LC50 value is the concentration of the compound leading to 50% net cell death.

The dose of 0.7 mM VPA has been chosen because it corresponds to plasma levels in patients treated for epilepsy, and it is able to inhibit histone deacetylation (Catalano et al. 2006). Moreover, a dose–response curve showed that VPA alone has no effect on cell growth up to the dose of 1.5 mM (Catalano et al. 2006).

As far as paclitaxel doses are concerned, the higher concentration used in our study (1 µM) is within the range of the clinically attainable plasma paclitaxel concentration ranging approximately from 0.045 to 5 µM for various infusion durations and dose regimens in patients (Wiernik et al. 1987).

Apoptosis detection

Cell death detection ELISA
For apoptosis studies, 1 x 103 cells were seeded in 96-well plates and treated with VPA and paclitaxel, using the same schedule as for the viability assay. After different treatments, apoptosis was evaluated using Cell Death Detection ELISA PLUS (Roche Applied Science) following the manufacturer’s instructions. Apoptosis was expressed as enrichment factor, calculated as a fraction of the absorbance of treated cells versus untreated controls.

Caspase activity assay
5 x 105 cells were seeded in 75 cm2 flasks and exposed to VPA and paclitaxel as above. After drug treatments, caspase 3 was determined using a colorimetric assay kit (R&D Systems Inc., Minneapolis, MN, USA). Briefly, cells were lysed and incubated with the colorimetric substrate DEVD-pNA for 2 h at 37 °C. After incubation, the chromophore was quantified spectrophotometrically at 405 nm.

Western blot analysis of tubulin acetylation

Western blot for acetylated {alpha}-tubulin was performed in CAL-62 cells treated with VPA, paclitaxel, or the combined treatment. In a first series of experiments, CAL-62 cells were treated with increasing doses of VPA (0.2–0.5–0.7–1–1.5 mM) for different times (ranging from 24 to 72 h). In a second series, cells were treated first with 0.7 mM VPA for 24 h and then with 0.01–0.1–1 µM paclitaxel. After treatment, cells were harvested and lysed in the presence of 200 µl radio immunoprecipitation assay (RIPA) buffer (1% NP40, 0.5% desoxycholate sodium, 0.1% SDS in PBS (pH 7.4) with 10 mg/ml phenylmethylsulphonyl fluoride, 30 µl/ml aprotinin, and 100 mM sodium orthovanadate) and incubated on ice for 30 min; cells were then centrifuged for 20 min at 15 000 g at 4 °C, and clear supernatants used. SDS-PAGE was performed on 10% gels, loading 20 µg protein/well. Separated proteins were electrotransferred onto polyvinglidine difluoride (PVDF) membrane and probed with a mouse monoclonal anti-acetyl-{alpha}-tubulin antibody (clone 6-11B-1, 1:8000 dilution, Sigma). The membrane was then stripped and reprobed with a mouse monoclonal anti-{alpha}-tubulin antibody (clone DM1A, 1:2000 dilution, Sigma) to check protein loading. Proteins were detected with Pierce Super Signal chemiluminescent substrate following the manufacturer’s instructions. Bands were photographed and analyzed using Kodak 1D Image Analysis software.

HDAC6 assay

The inhibitory effect of VPA (0.5–2 mM) on HDAC6 activity was tested on a recombinant HDAC6 protein obtained by BPS Bioscience (San Diego, CA, USA) and measured with a Fluorimetric Assay kit (Biomol, Plymouth, PA, USA) following manufacturer’s instructions. Briefly, in a 96-well plate, 30 nM HDAC6 was incubated with 30 µM Fluor de Lys substrate in HDAC assay buffer in the presence of VPA at various concentrations. Reaction was performed at 30 °C for 1 h and stopped by adding 50 µl developer plus 1 mg/ml Tricostatin A (TSA). After further 15-min incubation, plate was read by a Microplate Spectrophotometer (Mithras LB940, Berthold Technologies, Germany) at {lambda}excitation = 355 nm and {lambda}emission = 460 nm.

Statistical analysis

Data are expressed throughout as means ± S.E.M., calculated from at least three different experiments. In viability experiments, statistical comparison between cells treated with VPA plus paclitaxel and VPA alone was performed with the Mann–Whitney test. Comparison between groups was performed with ANOVA (one-way ANOVA) and the threshold of significance was calculated with the Bonferroni test. Statistical significance was set at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Effect of VPA on paclitaxel antitumor activity

Figure 1Go shows the effect on CAL-62 and ARO cell viability exerted by paclitaxel alone or after a 24 h pretreatment with VPA. Pretreatment of the cells with 0.7 mM VPA significantly increased paclitaxel effect starting at the concentration of 0.01 µM (P < 0.05). In both cell lines, the effect on cell viability obtained when VPA was added to cultures was the same as that obtained with a one-tenth or smaller dose of paclitaxel alone.


Figure 1
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  		Figure 1 Sensitizing effect of VPA to paclitaxel in anaplastic thyroid cancer cells. CAL-62 (upper panel) and ARO (lower panel) cells were incubated for 24 h with 0.7 mM VPA before the addition of paclitaxel (0.001–0.01–0.05–0.1–0.5–1 µM). After a further 72 h, cell viability was determined by the WST-1 method, and expressed as the ratio between treated cells and untreated controls (without paclitaxel or VPA).

 
As shown in Table 1Go, VPA improved both the cytostatic and cytotoxic activities of paclitaxel in CAL-62 and ARO cells.


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  		Table 1 GI50, total growth inhibition (TGI), and LC50 for paclitaxel (µM) after treatment with paclitaxel alone or combined with valproic acid (VPA)
 
Effect of VPA on paclitaxel-mediated apoptosis

Since our results indicated that pretreatment of CAL-62 and ARO cells with VPA sensitized cells to paclitaxel cytotoxicity, we investigated whether the same effect was detectable on apoptosis induction. As shownin Fig. 2Go and as we report elsewhere (Catalano et al. 2006), 0.7 mM VPA alone had no effect on apoptosis induction in these ATC cell lines. Nevertheless, it significantly enhanced paclitaxel-mediated apoptosis in both cell lines at all concentrations tested. The induction of apoptosis was demonstrated by quantification of nucleosome formation (Fig. 2A and BGo) and was confirmed by caspase 3 activation (Fig. 2C and DGo).


Figure 2
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  		Figure 2 Effect of VPA on paclitaxel-induced apoptosis. ELISA detection of DNA-histone complex. CAL-62 (A) and ARO (B) cells were treated with VPA (0.7 mM) for 24 h, followed by combined treatment with VPA and paclitaxel (0.01–1 µM) for a further 72 h. The enrichment factor was calculated as the ratio between the absorbance measurements of treated cells and the basal value (exposed to neither VPA nor paclitaxel). Detection of caspase 3 activation. CAL-62 (C) and ARO (D) cells were treated with VPA (0.7 mM) for 24 h, followed by combined treatment with VPA and paclitaxel (0.01–0.1–1 µM); after treatment, caspase 3 activity was measured as described in the text; activity of caspase in untreated cells was taken as 1. Results are expressed as means ± S.E.M.; n = 3. Significance versus cells not exposed to VPA: *P < 0.05; **P < 0.01; ***P < 0.001.

 
Effect of VPA and paclitaxel on tubulin acetylation

It has been reported that HDI may promote acetylation of nonhistone proteins, and that tubulin may also undergo acetylation as a consequence of HDI action (Blagosklonny et al. 2002). As reported in Fig. 3Go, VPA induced tubulin acetylation, the effect already being evident starting at 0.5 mM concentration and after 24 h treatment. Any significant further increase in tubulin acetylation was observed after exposure for longer times (data not shown). Tubulin acetylation is mainly controlled by HDAC6 (Zhang et al. 2003). Here, we demonstrate that VPA, a class I/II HDI, is able to inhibit HDAC6 activity (as reported in Fig. 3CGo).


Figure 3
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  		Figure 3 Effect of VPA on tubulin acetylation. A representative experiment of the accumulation of acetylated tubulin in CAL-62, treated with 0.2–1.5 mM VPA for 24 h (A), assessed by western blotting with an anti-acetyl-tubulin antibody. Equal loading and transfer were verified by reprobing the membranes with an anti-tubulin antibody. Histogram (B): semiquantitative analysis of western blotting results. Net intensity was determined as the ratio between treated cells and untreated control. Results are expressed as means ± S.E.M.; n = 3. Effect of VPA on HDAC6 activity (C). The activity was determined in the presence of 0.5–2 mM VPA by deacetylation of fluorescence-labeled acetylated lysyl substrate. Results are expressed as means ± S.E.M.; n = 3.

 
Moreover, 0.7 mM VPA enhanced the ability of both 0.01 and 0.1 µM paclitaxel to induce tubulin acetylation (as shown in Fig. 4Go). Interestingly, 0.7 mM VPA had only a slight effect on the level of tubulin acetylation induced by 1 µM paclitaxel. It may thus be suggested that tubulin acetylation has almost reached its plateau with 1 µM paclitaxel treatment, and therefore, its acetylation level cannot be significantly enhanced by further VPA.


Figure 4
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  		Figure 4 Combined effect of VPA plus paclitaxel on tubulin acetylation. Arepresentative experiment of the accumulation of acetylated tubulin in CAL-62 cells, treated with VPA and paclitaxel (0.01–0.1–1 µM; A), assessed by western blotting with an anti-acetyl-tubulin antibody. Equal loading and transfer were verified by reprobing the membranes with an anti-tubulin antibody. Histogram (B): semiquantitative analysis of western blotting results. Net intensity was determined as the ratio between treated cells and untreated control (basal). Results are expressed as means ± S.E.M.; n = 3. Significance versus cells not exposed to VPA: #P < 0.05; ##P < 0.001.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
We show in this study that the combination of VPA with paclitaxel enhances paclitaxel cytostatic and cytotoxic activity in two different ATC cell lines (CAL-62 and ARO). Notably, in the presence of VPA, we obtained the same effect on cell viability with a one-tenth dose of paclitaxel when compared with the dose needed when the drug is used alone. The effect is reached with VPA at a dose of 0.7 mM, which corresponds to plasma levels in patients treated for epilepsy and is without any serious side effects.

Apoptosis induction mediates paclitaxel cytotoxicity, and here we show that VPA treatment markedly increases paclitaxel-induced apoptosis, as demonstrated by both cytoplasmatic nucleosome formation and caspase 3 activation. Suppression of microtubule dynamics is recognized as the mechanism by which paclitaxel blocks mitosis and kills tumor cells (Jordan & Wilson 2004): rapid dynamics ensures timely and accurate chromosome movement. The suppression of spindle microtubule dynamics might slow or block mitosis at the metaphase–anaphase transition, and facilitate apoptotic cell death. The effect on microtubule dynamics is at least partially due to paclitaxel effect on tubulin acetylation (Piperno et al. 1987), an established marker of microtubule stability (Schiff & Horwitz 1980, Jordan et al. 1993, Mollinedo & Gajate 2003). Here, we show that VPA is able not only to induce tubulin acetylation, when used alone, but also to markedly enhance the acetylating activity of paclitaxel. This latter effect may be related to a more efficient binding of paclitaxel to microtubules, depending on the VPA-induced suppression of microtubule dynamics (Zhou et al. 2004). Zhang et al.(2003) reported that HDAC6 is a microtubule-associated protein capable of deacetylating {alpha}-tubulin in vitro and in vivo, and that HDI treatment leads to hyperacetylation of tubulin and microtubules. We here demonstrate that VPA is able to affect HDAC6 activity; our results being in line with those obtained by Gottlicher, which reported an IC50 = 2.4 mM (Gottlicher et al. 2001), whereas Gurvich et al.(2004) measured an IC50 > 20 mM. Our data clearly show that VPA induces tubulin acetylation and maximally potentiates the acetylating activity of paclitaxel. The capability to induce acetylation of tubulin (Blagosklonny et al. 2002) has also been documented for TSA, a HDI, whose clinical use is hampered by its high toxicity (Sandor et al. 2002).

Besides affecting tubulin acetylation, the drug combination might also act on the mitotic spindle checkpoint, contributing to enhancing paclitaxel cytotoxicity and increasing drug selectivity on tumor cells. As we report elsewhere (Catalano et al. 2006), VPA also enhances the sensitivity of the anaplastic tumor thyroid cell lines to doxorubicin, a DNA-targeted drug widely used in treating ATC; we suggest that impairment of cell-cycle checkpoints might contribute to the enhanced killing activity of the combined treatment. In line with this observation, Dowling et al.(2005) reported that TSA, by inhibiting histone deacetylation, affects the expression of genes that encode for mitotic checkpoint proteins, and hampers mitotic checkpoint surveillance and regulation of post-mitotic progression.

Although we demonstrated that the effects of valproate are through tubulin acetylation, potential effects on the membrane transporters responsible for multidrug resistance cannot be excluded. However, recent studies have shown that HDIs increase the expression of MDR1 (Tabe et al. 2006) and its product P-glycoprotein (Robey et al. 2006).

The clinical use of paclitaxel is severely hampered, especially in older patients with thyroid anaplastic carcinoma, by its several dose-dependent side effects, i.e. myelotoxicity, neuropathy, anaphylaxis, and severe hypersensitivity reactions. Mechanisms underlying paclitaxel toxic effects still remain largely unknown; however, it has to be remarked that they chiefly depend upon high-dose regimes, and that a potential cofactor for these damages is the polyoxyethylated castor oil vehicle, Cremophor EL, possibly inducing peroxidation products affecting neurons (Mielke et al. 2006). As far as toxic effects mediated by microtubule alterations are concerned, it has been reported that they mainly depend on microtubule polymerization (Zhou et al. 2004), whereas apoptotic cell death in tumor cells already appears after the suppression of spindle microtubule dynamics (Jordan et al. 1996, Jordan & Wilson 2004), without any increase of microtubule polymer mass formation. At the peak and steady-state plasma concentrations reached by the doses of paclitaxel in current clinical use (Wiernik et al. 1987), the effect on microtubule polymer mass formation (Derry et al. 1995), and thus toxicity (Jordan et al. 1996), might be prevalent. Therefore, the use of VPA, a drug that may consent to reduce the paclitaxel dose maintaining the same killing effect on tumor cells, might allow more prolonged and effective treatment. Nevertheless, on the basis of the present results, VPA-induced tubulin hyperacetylation also on non-target tissues cannot be excluded, and translational and clinical studies will ultimately determine the clinical safety of this combination therapy.

Collectively, our data suggest a mechanistic link between HDAC inhibition, tubulin acetylation, and the VPA-induced enhancement of paclitaxel effects, and might provide insight into the design offuture combination therapies, which include microtubule-targeting drugs.


   Acknowledgements
 
The authors thank Laura Barberis for her technical support with HDAC6 experiments and Gabriele Brondino for statistical analysis. This study was supported by the Special Project ‘Oncology’, Compagnia San Paolo, Turin, by MIUR, and by Regione Piemonte. The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Ain KB, Egorin MJ & DeSimone PA 2000 Treatment of anaplastic thyroid carcinoma with paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group. Thyroid 10 587–594.[Web of Science][Medline]

Blagosklonny MV, Robey R, Sackett DL, Du L, Traganos F, Darzynkiewicz Z, Fojo T & Bates SE 2002 Histone deacetylase inhibitors all induce p21 but differentially cause tubulin acetylation, mitotic arrest, and cytotoxicity. Molecular Cancer Therapeutics 1 937–941.[Abstract/Free Full Text]

Brignardello E, Gallo M, Baldi I, Palestini N, Piovesan A, Grossi E, Ciccone G & Boccuzzi G 2007 Anaplastic thyroid carcinoma: clinical outcome of 30 consecutive patients referred to a single institution in the past 5 years. European Journal of Endocrinology 156 425–430.[Abstract/Free Full Text]

Catalano MG, Fortunati N, Pugliese M, Costantino L, Poli R, Bosco O & Boccuzzi G 2005 Valproic acid induces apoptosis and cell cycle arrest in poorly differentiated thyroid cancer cells. Journal of Clinical Endocrinology and Metabolism 90 1383–1389.[Abstract/Free Full Text]

Catalano MG, Fortunati N, Pugliese M, Poli R, Bosco O, Mastrocola R, Aragno M & Boccuzzi G 2006 Valproic acid, a histone deacetylase inhibitor, enhances sensitivity to doxorubicin in anaplastic thyroid cancer cells. Journal of Endocrinology 191 465–472.[Abstract/Free Full Text]

Copland JA, Marlow LA, Kurakata S, Fujiwara K, Wong AK, Kreinest PA, Williams SF, Haugen BR, Klopper JP & Smallridge RC 2006 Novel high-affinity PPARgamma agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via p21WAF1/CIP1. Oncogene 25 2304–2317.[CrossRef][Web of Science][Medline]

Derry WB, Wilson L & Jordan MA 1995 Substoichiometric binding of taxol suppresses microtubule dynamics. Biochemistry 34 2203–2211.[CrossRef][Medline]

Dowling M, Voong KR, Kim M, Keutmann MK, Harris E & Kao GD 2005 Mitotic spindle checkpoint inactivation by trichostatin a defines a mechanism for increasing cancer cell killing by microtubule-disrupting agents. Cancer Biology & Therapy 4 197–206.[Web of Science][Medline]

Fortunati N, Catalano MG, Arena K, Brignardello E, Piovesan A & Boccuzzi G 2004 Valproic acid induces the expression of the Na+/I– symporter and iodine uptake in poorly differentiated thyroid cancer cells. Journal of Clinical Endocrinology and Metabolism 89 1006–1009.[Free Full Text]

Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci PG et al. 2001 Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO Journal 20 6969–6978.[CrossRef][Web of Science][Medline]

Gurvich N, Tsygankova OM, Meinkoth JL & Klein PS 2004 Histone deacetylase is a target of valproic acid-mediated cellular differentiation. Cancer Research 64 1079–1086.[Abstract/Free Full Text]

Jordan MA & Wilson L 2004 Microtubules as a target for anticancer drugs. Nature Review Cancer 4 253–265.[CrossRef]

Jordan MA, Toso RJ, Thrower D & Wilson L 1993 Mechanism of mitotic block and inhibition of cell proliferation by taxol at low concentrations. PNAS 90 9552–9556.[Abstract/Free Full Text]

Jordan MA, Wendell K, Gardiner S, Derry WB, Copp H & Wilson L 1996 Mitotic block induced in HeLa cells by low concentrations of paclitaxel (Taxol) results in abnormal mitotic exit and apoptotic cell death. Cancer Research 56 816–825.[Abstract/Free Full Text]

Kebebew E, Greenspan FS, Clark OH, Woeber KA & McMillan A 2005 Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer 103 1330–1335.[CrossRef][Web of Science][Medline]

Marchion DC, Bicaku E, Daud AI, Richon V, Sullivan DM & Munster PN 2004 Sequence-specific potentiation of topoisomerase II inhibitors by the histone deacetylase inhibitor suberoylanilide hydroxamic acid. Journal of Cellular Biochemistry 92 223–237.[CrossRef][Web of Science][Medline]

Marchion DC, Bicaku E, Daud AI, Sullivan DM & Munster PN 2005 Valproic acid alters chromatin structure by regulation of chromatin modulation proteins. Cancer Research 65 3815–3822.[Abstract/Free Full Text]

Markman M 2003 Managing taxane toxicities. Supportive Care in Cancer 11 144–147.[Web of Science][Medline]

Marks PA, Richon VM, Breslow R & Rifkind RA 2001 Histone deacetylase inhibitors as new cancer drugs. Current Opinion in Oncology 13 477–483.[CrossRef][Web of Science][Medline]

Matsuyama A, Shimazu T, Sumida Y, Saito A, Yoshimatsu Y, Seigneurin-Berny D, Osada H, Komatsu Y, Nishino N, Khochbin S et al. 2002 In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation. EMBO Journal 21 6820–6831.[CrossRef][Web of Science][Medline]

Mielke S, Sparreboom A & Mross K 2006 Peripheral neuropathy: a persisting challenge in paclitaxel-based regimes. European Journal of Cancer 42 24–30.[CrossRef][Web of Science][Medline]

Mollinedo F & Gajate C 2003 Microtubules, microtubule-interfering agents and apoptosis. Apoptosis 8 413–450.[CrossRef][Web of Science][Medline]

Pasieka JL 2003 Anaplastic thyroid cancer. Current Opinion in Oncology 15 78–83.[CrossRef][Web of Science][Medline]

Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA & Klein PS 2001 Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. Journal of Biological Chemistry 276 36734–36741.[Abstract/Free Full Text]

Piperno G, LeDizet M & Chang XJ 1987 Microtubules containing acetylated alpha-tubulin in mammalian cells in culture. Journal of Cell Biology 104 289–302.[Abstract/Free Full Text]

Robey RW, Zhan Z, Piekarz RL, Kayastha GL, Fojo T & Bates SE 2006 Increased MDR1 expression in normal and malignant peripheral blood mononuclear cells obtained from patients receiving depsipeptide (FR901228, FK228, NSC630176). Clinical Cancer Research 12 1547–1555.[Abstract/Free Full Text]

Rosato RR & Grant S 2003 Histone deacetylase inhibitors in cancer therapy. Cancer Biology and Therapy 2 30–37.

Sandor V, Bakke S, Robey RW, Kang MH, Blagosklonny MV, Bender J, Brooks R, Piekarz RL, Tucker E, Figg WD et al. 2002 Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clinical Cancer Research 8 718–728.[Abstract/Free Full Text]

Schiff PB & Horwitz SB 1980 Taxol stabilizes microtubules in mouse fibroblast cells. PNAS 77 1561–1565.[Abstract/Free Full Text]

Tabe Y, Konopleva M, Contractor R, Munsell M, Schober WD, Jin L, Tsutsumi-Ishii Y, Nagaoka I, Igari J & Andreeff M 2006 Up-regulation of MDR1 and induction of doxorubicin resistance by histone deacetylase inhibitor depsipeptide (FK228) and ATRA in acute promyelocytic leukemia cells. Blood 107 1546–1554.[Abstract/Free Full Text]

Vigushin DM & Coombes RC 2002 Histone deacetylase inhibitors in cancer treatment. Anticancer Drugs 12 1–13.

Vivat-Hannah V, You D, Rizzo C, Daris JP, Lapointe P, Zusi FC, Marinier A, Lorenzi MV & Gottardis MM 2001 Synergistic cytotoxicity exhibited by combination treatment of selective retinoid ligands with taxol (Paclitaxel). Cancer Research 61 8703–8711.[Abstract/Free Full Text]

Wiernik PH, Schwartz EL, Strauman JJ, Dutcher JP, Lipton RB & Paietta E 1987 Phase I clinical and pharmacokinetic study of taxol. Cancer Research 47 2486–2493.[Abstract/Free Full Text]

Yeung SC, Xu G, Pan J, Christgen M & Bamiagis A 2000 Manumycin enhances the cytotoxic effect of paclitaxel on anaplastic thyroid carcinoma cells. Cancer Research 60 650–656.[Abstract/Free Full Text]

Zhang Y, Li N, Caron C, Matthias G, Hess D, Khochbin S & Matthias P 2003 HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo. EMBO Journal 22 1168–1179.[CrossRef][Web of Science][Medline]

Zhou J, Liu M, Aneja R, Chandra R & Joshi HC 2004 Enhancement of paclitaxel-induced microtubule stabilization, mitotic arrest, and apoptosis by the microtubule-targeting agent EM012. Biochemical Pharmacology 68 2435–2441.[CrossRef][Web of Science][Medline]




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