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Results for “Tubulin Modulators”

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PubMed2005

Synthesis and structure-activity relationships of 1,2,4-triazoles as a novel class of potent tubulin polymerization inhibitors.

A novel triazole-containing chemical series was shown to inhibit tubulin polymerization and cause cell cycle arrest in A431 cancer cells with EC(50) values in the single digit nanomolar range. Binding experiments demonstrated that representative active compounds of this class compete with colchicine for its binding site on tubulin. The syntheses and structure-activity relationship studies for the triazole derivatives are described herein.

Antineoplastic Agents↗
PubMed2006

2-Methoxyestradiol and paclitaxel have similar effects on the cell cycle and induction of apoptosis in prostate cancer cells.

2-Methoxyestradiol (2-ME) is an endogenous metabolite of estradiol with promise for cancer chemotherapy, including advanced prostate cancer. We have focused on events related to cell cycle arrest (G1 and G2/M) and induction of apoptosis in human prostate cancer cells. Treatment with 2-ME increased cyclin B1 protein and its associated kinase activity followed by later inhibition of cyclin A-dependent kinase activity and induction of apoptosis. Similar results were obtained with paclitaxel (taxol), a clinically relevant agent used to treat advanced prostate cancer. Cyclin-dependent kinase inhibitors prevented 2-ME and paclitaxel-mediated increase in cyclin B1-dependent kinase activity and blocked induction of apoptosis. Reduction of X-linked inhibitor of apoptosis (XIAP) protein by 2-ME and paclitaxel correlated with increased apoptosis. Lower doses of 2-ME and paclitaxel resulted in G1 (but not G2/M) cell cycle arrest in the p53 wild type LNCaP cell line, but with minimal induction of apoptosis. We suggest that 2-ME and paclitaxel-mediated induction of apoptosis in prostate cancer cells requires activation of cyclin B1-dependent kinase that arrests cells in G2/M and subsequently leads to the induction of apoptotic cell death.

2-Methoxyestradiol↗
PubMed2006

Antiproliferative effect of polyphenols and sterols of virgin argan oil on human prostate cancer cell lines.

BACKGROUND: The aim of our study has to evaluate the antiproliferative effect of polyphenols and sterols extracted from the virgin argan oil on three human prostatic cell lines (DU145, LNCaP, and PC3). METHODS: Cytotoxicity, anti-proliferative effects and nuclear morphological changes of cells were analyzed after treatment with sterols and polyphenols. The results were compared to 2-methoxyestradiol (2ME(2)) as positive control. RESULTS: Polyphenols and sterols of virgin argan oil and 2ME(2) exhibited a dose-response cytotoxic effect and antiproliferative action on the three tested cell lines. The antiproliferative effect of polyphenols was similar for the DU145 and LNCaP cell lines; the GI(50) (defined as the concentration inhibiting growth by 50% in comparison with the control) was respectively 73 and 70microg/ml. The antiproliferative effect of sterols was 46 and 60microg/ml as GI(50) for the DU145 and LNCaP cell lines. For the PC3 cell line, the best antiproliferative effect was obtained by argan sterols with GI(50)=43microg/ml. On the other hand, the nuclear morphology analyses have shown an increased proportion of pro-apoptotic of nuclei in LNCaP cell treated with IC(50) of polyphenols or sterols compared to control cells. Our results show for the first time the antiproliferative and pro-apoptotic effects of polyphenols and sterols extracted from virgin argan oil and confirm the antiproliferative and pro-apoptotic effects of 2ME(2) on prostate cancer cell lines. CONCLUSION: These data suggest that argan oil may be interesting in the development of new strategies for prostate cancer prevention.

2-Methoxyestradiol↗
PubMed2004

The anticancer natural product pironetin selectively targets Lys352 of alpha-tubulin.

Pironetin is a potent inhibitor of tubulin assembly and arrests cell cycle progression in M phase. Analyses of its structure-activity relationships suggested that pironetin covalently binds tubulin. To determine the binding site of pironetin, we synthesized biotinylated pironetin, which inhibited tubulin assembly both in vitro and in situ. The biotinylated pironetin selectively and covalently bound with tubulin. Partial digestion of biotinylated pironetin-treated tubulin by several proteases revealed that the binding site is the C-terminal portion of alpha-tubulin. By systematic alanine scanning, the pironetin binding site was determined to be Lys352 of alpha-tubulin. Lys352 is located at the entrance of a small pocket of alpha-tubulin, and this pocket faces the beta-tubulin of the next dimer. This is the first compound that covalently binds to the alpha subunit of tubulin and Lys352 of alpha-tubulin and inhibits the interaction of tubulin heterodimers.

Amino Acid Sequence↗
PubMed2005

New cytotoxic agents: a review of the literature.

The goal of treatment for patients with advanced cancer is to prolong survival, control symptoms, and reduce disease-related complications. Despite the introduction of many cytotoxic agents during the past decade, only modest improvement in survival has been achieved. In order to urgently improve these situations, new cytotoxic agents as well as molecular-targeted agents are now under investigation. In this article, we reviewed the latest information regarding antitumor activity, toxicity, pharmacokinetics, and clinical application of the new cytotoxic agents.

Antimetabolites, Antineoplastic↗
PubMed2007

Microtubule dynamics in root hairs of Medicago truncatula.

The microtubular cytoskeleton plays an important role in the development of tip-growing plant cells, but knowledge about its dynamics is incomplete. In this study, root hairs of the legume Medicago truncatula have been chosen for a detailed analysis of microtubular cytoskeleton dynamics using GFP-MBD and EB1-YFP as markers and 4D imaging. The microtubular cytoskeleton appears mainly to be composed of bundles which form tracks along which new microtubules polymerise. Polymerisation rates of microtubules are highest in the tip of growing root hairs. Treatment of root hairs with Nod factor and latrunculin B result in a twofold decrease in polymerisation rate. Nonetheless, no direct, physical interaction between the actin filament cytoskeleton and microtubules could be observed. A new picture of how the plant cytoskeleton is organised in apically growing root hairs emerges from these observations, revealing similarities with the organisation in other, non-plant, tip-growing cells.

Actins↗
PubMed2004

Synthesis, cytotoxicity, and inhibitory effects on tubulin polymerization of a new 3-heterocyclo substituted 2-styrylquinazolinones.

In order to study the influence of 3-substitution on the cytotoxic activity of 2-styrylquinazolinones, new 6-chloro-2-styryl-3-(heteroaryl)-4(3H)-quinazolinones were synthesized by refluxing equimolar amounts of 6-chloro-2-methyl-3-(heteroaryl)-4(3H)-quinazolinones and benzaldehyde in glacial acetic acid. At 1 microg ml(-1) concentration, almost all 2-styrylquinazolinones showed some cytotoxic activity against the L1210 and K562 leukemia cell lines. However, only 6-chloro-2-styryl-3-(pyrimidin-2yl)-4(3H)-quinazolinone inhibited the growth of these cells by over 50%. This last compound was also the only member of the series that inhibited tubulin polymerization, with an IC(50) value of 5.8 versus 3.2 microM for colchicine. It was also examined for effects on the growth of human MCF7 breast carcinoma cells and Burkitt lymphoma CA46 cells, which had IC(50) values of 0.34 and 1.0 microM, respectively. At 10 microM 6-chloro-2-styryl-3-(pyrimidin-2yl)-4(3H)-quinazolinone induced G2/M arrest (66%) in Burkitt cells, with a mitotic index of 20%. At 3.4 microM, it caused disruption of the cellular microtubule system of the MCF7 cells. Both these cellular effects are consistent with its mechanism of action resulting from its inhibitory effect on tubulin assembly.

Animals↗
PubMed2005

Synthesis and evaluation of double bond substituted combretastatins.

A series of combretastatins substituted with epoxides, amides and small alkyl groups has been synthesised and evaluated for cytotoxicity and their ability to inhibit the assembly of tubulin. The methyl and ethyl substituted phenols 36, 44 have shown potent antimitotic effects whilst exhibiting reduced cytotoxicity.

Amides↗
PubMed2006

Pyrimido[4,5-c]quinolin-1(2H)-ones as a novel class of antimitotic agents: Synthesis and in vitro cytotoxic activity.

Several 2-amino-pyrimido[4,5-c]quinolin-1(2H)-ones variously substituted at positions 3, 5, and 9 were prepared from their corresponding lactones. The target compounds were investigated for in vitro cytotoxic activity against a panel of human cancer cell lines, namely, lung fibrosarcoma HT-1080, colon adenocarcinoma HT-29, and breast carcinoma MDA-MB-231. Analysis of data revealed that the presence of chloro at position 9 has a major positive impact on cytotoxic activity. Additional halogen substitution at the para position of the 3-phenyl group further enhances activity. Furthermore, compound (25) was found to dose-dependently inhibit tubulin polymerization. In accordance, flow cytometric analysis of the most potent compounds (23-26) indicated that the tested compounds induce cell cycle arrest in the G(2)/M phase. The obtained results introduce the rarely described pyrimido[4,5-c]quinolin-1(2H)-one ring system as a new scaffold for promising antimitotic agents.

Antimitotic Agents↗
PubMed2006

Differential effects of hydroxyacetophenone analogues on the transcytotic vesicular pathway in rat liver.

Insertion of transporter proteins into the apical canalicular membrane via vesicular transport is one of several choleretic mechanisms. Based on different choleretic activities of hydroxyacetophenone analogues including 4-mono; 2,6-di and 2,4,6-trihydroxy-acetophenone (MHA, DHA and THA), the present study aims to determine if these compounds stimulated vesicular transport in hepatocytes. Hydroxyacetophenone was continuously infused into the duodenum of the bile fistula rat. Bile flow rate was allowed to stabilize and then followed by an intraportal injection of horseradish peroxidase, a marker of the transcytotic vesicle pathway. MHA which stimulates bile acid independent flow, showed a dose-dependent increase in both the early (paracellular) and late (transcellular) peak of horseradish peroxidase excretion in bile. THA, which stimulates both bile acid dependent flow and bile acid independent flow, did not alter the pattern of horseradish peroxidase excretion into bile. However, DHA, which is more hydrophobic and increases only bile acid dependent flow, decreased the late peak. The stimulating effects of MHA on bile flow and horseradish peroxidase excretion were markedly inhibited by colchicine, suggesting that its choleretic action involves stimulation of exocytosis, as well as increase in paracellular permeability. In contrast, the lack of a stimulatory effect of THA and DHA on biliary horseradish peroxidase excretion suggested that their choleretic action is not associated with vesicular exocytosis. These results demonstrate a variable effect of hydroxyacetophenones on the transcytotic vesicular pathway reflecting different choleretic mechanisms and therapeutic potential.

Acetophenones↗
PubMed2006

Taxol and tau overexpression induced calpain-dependent degradation of the microtubule-destabilizing protein SCG10.

Microtubule-stabilizing and -destabilizing proteins play a crucial role in regulating the dynamic instability of microtubules during neuronal development and synaptic transmission. The microtubule-destabilizing protein SCG10 is a neuron-specific protein implicated in neurite outgrowth. The SCG10 protein is significantly reduced in mature neurons, suggesting that its expression is developmentally regulated. In contrast, the microtubule-stabilizing protein tau is expressed in mature neurons and its function is essential for the maintenance of neuronal polarity and neuronal survival. Thus, the establishment and maintenance of neuronal polarity may down-regulate the protein level/function of SCG10. In this report, we show that treatment of PC12 cells and neuroblastoma cells with the microtubule-stabilizing drug Taxol induced a rapid degradation of the SCG10 protein. Consistently, overexpression of tau protein in neuroblastoma cells also induced a reduction in SCG10 protein levels. Calpain inhibitor MDL-28170, but not caspase inhibitors, blocked a significant decrease in SCG10 protein levels. Collectively, these results indicate that tau overexpression and Taxol treatment induced a calpain-dependent degradation of the microtubule-destabilizing protein SCG10. The results provide evidence for the existence of an intracellular mechanism involved in the regulation of SCG10 upon microtubule stabilization.

Animals↗
PubMed2006

2-methoxyestradiol reduces cerebral vasospasm after 48 hours of experimental subarachnoid hemorrhage in rats.

2-Methoxyestradiol (2ME2), a naturally occurring metabolite of estradiol, is known to have antiproliferative, antiangiogenic, and antiproapoptotic activities. Mechanistically, 2ME2 has been shown to downregulate hypoxia-inducible factor 1alpha (HIF-1alpha). We hypothesized that hypoxia in the major cerebral arteries might activate a unique signaling pathway, hypoxia-inducible factor-1alpha (HIF-1alpha), to produce or enhance cerebral vasospasm after subarachnoid hemorrhage (SAH). Sprague-Dawley male rats (n = 70) were randomly divided into 5 groups: Sham operated, SAH without treatment, SAH treated with vehicle (DMSO), SAH treated with two HIF-1alpha inhibitors, 2ME2, and D609 (positive control of 2ME2). SAH model was produced by middle cerebral artery perforation. 2ME2 and D609 were administered intraperitoneal at 1 h after SAH; rats were sacrificed after 48 h of SAH. Thick blood clot was observed around basilar artery under arachnoids in all animals except Sham group; severe morphological vasospasm was observed in basilar arteries in SAH and SAH+DMSO rats, and the mild vasospasm in rats treated with 2ME2 and D609; 2ME2 and D609 reduced the activity of HIF-1alpha in the basilar arteries by HIF-1alpha DuoSet ELISA; reduce the expression of HIF-1alpha, VEGF, BNIP3 and PCNA in basilar arteries by Western blotting and immunohistochemical staining. In addition, it decreased the mortality and improved the neurological deficits. In conclusion, 2ME2 is a powerful agent to reduce cerebral vasospasm by inhibiting HIF-1alpha activity and the expression of VEGF as its downstream, suppressing endothelium and VSMCs apoptosis via BNIP3 pathway, and attenuating vasoproliferation.

2-Methoxyestradiol↗
PubMed2006

Microtubule disruption, not calpain-dependent loss of MAP2, contributes to enduring NMDA-induced dendritic dysfunction in acute hippocampal slices.

Brief exposure to excitotoxic agonists can result in substantial loss of the microtubule-associated protein MAP2 from neuronal dendrites, and accumulation in somata. A possible mechanism underling MAP2 loss is the activation of the calcium-dependent protease calpain by excessive dendritic Ca2+-loading. The present study examined mechanisms of MAP2 redistribution and loss of synaptic efficacy in the CA1 region of acutely prepared hippocampal slices. Brief NMDA exposure resulted in persistent and profound inhibition of postsynaptic potentials, and loss of MAP2 from dendritic compartments. When Ca2+ was removed during NMDA exposure, synaptic potentials recovered significantly during NMDA washout, and MAP2 loss was reduced. Calpain inhibition with MDL 28,170 (20 microM) did not prevent the loss of synaptic potentials, nor did it attenuate the initial aggregation of MAP2 into irregular dendritic swellings. However MDL 28,170 did reduce subsequent MAP2 loss from abnormal dendritic aggregates. Pre-exposure of slices to taxol (100 nM) effectively prevented microtubule depolymerization following NMDA exposure, as well as MAP2 disorganization and loss from apical dendrites. Slices treated with taxol also exhibited substantial recovery of synaptic potentials after transient NMDA stimulus. These results demonstrate a close correspondence between the maintained localization of MAP2 in apical dendrites and the recovery of postsynaptic potentials following transient NMDA exposure. In addition, it appears that rather than underlying the initial disruption of microtubule structure via MAP2 proteolysis, calpain activity instead may contribute to the degradation of irregularly aggregated MAP2 observed following microtubule depolymerization.

Animals↗
PubMed2006

Leishmania tarentolae: purification and characterization of tubulin and its suitability for antileishmanial drug screening.

Previously, tubulin has been purified from Leishmania amazonensis and used to identify novel molecules with selective antimitotic activity. However, L. amazonensis is pathogenic and requires a relatively expensive medium for large-scale cultivation. Herein, the purification and characterization of tubulin from the non-pathogenic Leishmania tarentolae is reported, together with the sequence of alpha- and beta-tubulin from this organism. This protein was purified by sonication, diethylaminoethyl-Sepharose chromatography, and one assembly disassembly cycle in 1% overall recovery based on total cellular protein. Leishmania tarentolae tubulin was indistinguishable from the corresponding L. amazonensis protein in terms of binding affinity for dinitroaniline sulfanilamides and sensitivity to assembly inhibition by these compounds. The amino acid sequences derived from the L. tarentolae alpha- and beta-tubulin genes were 99.6 and 99.4% identical to the corresponding amino acid sequences from the Leishmania major Friedlin strain. These results indicate that tubulin from L. tarentolae is suitable for use in drug screening.

Amino Acid Sequence↗
PubMed2006

Active ammonia absorption in the midgut of the Tobacco hornworm Manduca sexta L.: transport studies and mRNA expression analysis of a Rhesus-like ammonia transporter.

In this study the mid- and hindgut of Manduca sexta larvae were tested for their ammonia transport properties using a custom-made Ussing chamber. In the presence of 0.1 mmoll(-1) ammonia on both sides of the isolated epithelium, active transepithelial ammonia absorption (aTEPA) was observed in all midgut sections, with greatest transport rates (ca. 140 nmol cm(-2)h(-1)) detected in the median midgut. The hindgut showed no aTEPA. In the median midgut inhibition of energy metabolism by azide blocked aTEPA completely, whereas inhibition of vacuolar H(+)-ATPase by bafilomycin A(1) reduced the active transport by 50%. The imposition of a luminal-directed NH(3)-gradient (pH 6.5 apical, pH 8.5 basal) lowered the aTEPA by approximately 50% but did not reverse its direction. Apical addition of amiloride reduced aTEPA by 90%, suggesting a role of carrier-mediated ammonia transport across the apical membrane via a member of the NHE family. Inhibition of the microtubule network by colchicine reduced aTEPA by ca. 50%. In contrast, blocking basal K(+) channels by Ba(2+) had no effect on aTEPA. Using molecular methods, evidence for intestinal expression of a Rhesus-like ammonia transporter (RhMS) was found with low mRNA expression in midgut tissues, but high expression levels in the hindgut, Malpighian tublules and ganglia.

Amiloride↗
PubMed2006

Formulation of sustained release nanoparticles loaded with a tripentone, a new anticancer agent.

The purpose of the present work is to develop nanoparticles of a new antitubulin agent of the family of tripentones by means of a phase inversion process. Dynamic light scattering, transmission electron microscopy and zeta-potential measurements were used to characterize tripentone loaded nanoparticles. From interfacial tension measurements and from the study of the rheological interfacial properties of the tripentone at the Labrafac-Solutol interface, the fraction of tripentone initially present in Labrafac would stay in the oily core of nanocapsules. Moreover, the interpenetration of some tripentone molecules within the surfactant units helps to the stabilization of the formulated nanoparticles. The encapsulation efficiency was determined by high performance liquid chromatography (HPLC) and was found to be above 95%. In vitro release studies were carried out in blank nanoparticles containing phosphate buffer, pH 7.4, at 37 degrees C. The drug release kinetics was measured by HPLC. Antiproliferative activity studies on L1210 cells showed that the cytotoxic activity of tripentone was totally recovered after encapsulation of the antitubulin agent in lipid nanoparticles. This study shows that lipid nanocapsules could be a promising and effective carrier for tripentone delivery in the treatment of cancers.

Animals↗
PubMed2005

Solidification/stabilization of arsenic containing solid wastes using portland cement, fly ash and polymeric materials.

Stabilization/solidification (S/S) is used as a pre-landfill waste treatment technology that aims to make hazardous industrial wastes safe for disposal. Cement-based solidification/stabilization technology is widely used because it offer assurance of chemical stabilization of many contaminants and produce a stable form of waste. The leaching behavior of arsenic from a solidified/stabilized waste was studied to obtain information about their potential environmental risk. Activated alumina (AA) contaminated with arsenic was used as a waste, which was stabilized/solidified (S/S) using ordinary portland cement (C), fly ash (FA), calcium hydroxide (CH) and various polymeric materials such as polystyrene and polymethyl methacrylate (PMMA). Toxicity characteristics leaching procedure (TCLP) and semi-dynamic leach tests were conducted to evaluate the leaching behavior of arsenic. Formations of calcite along with precipitate formation of calcium arsenite were found to be responsible for low leaching of arsenic from the stabilized/solidified samples. Effective diffusivity of arsenic ion from the matrix and leachablity index was also estimated. Minimum leaching of the contaminant was observed in matrix having AA+C+FA+CH due to the formation of calcite.

Aluminum Oxide↗