Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Tubulin Modulators”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources

Hypersensitivity to cytoskeletal antagonists demonstrates microtubule-microfilament cross-talk in the control of root elongation in Arabidopsis thaliana.

Elongation of diffusely expanding plant cells is thought to be mainly under the control of cortical microtubules. Drug treatments that disrupt actin microfilaments, however, can reduce elongation and induce radial swelling. To understand how microfilaments assist growth anisotropy, we explored their functional interactions with microtubules by measuring how microtubule disruption affects the sensitivity of cells to microfilament-targeted drugs. We assessed the sensitivity to actin-targeted drugs by measuring the lengths and diameters of expanding roots and by analysing microtubule and microfilament patterns in the temperature-sensitive Arabidopsis thaliana mutant microtubule organization 1 (mor1-1), along with other mutants that constitutively alter microtubule arrays. At the restrictive temperature of mor1-1, root expansion was hypersensitive to the microfilament-disrupting drugs latrunculin B and cytochalasin D, while immunofluorescence microscopy showed that low doses of latrunculin B exacerbated microtubule disruption. Root expansion studies also showed that the botero and spiral1 mutants were hypersensitive to latrunculin B. Hypersensitivity to actin-targeted drugs is a direct consequence of altered microtubule polymer status, demonstrating that cross-talk between microfilaments and microtubules is critical for regulating anisotropic cell expansion.

Actin Cytoskeleton↗

New agents for the treatment of ovarian cancer: the next generation.

Ovarian cancer shares many important characteristics with more common malignancies including breast, lung, and colon cancer. The relative chemosensitivity of ovarian cancer and other aspects of its unique biology provide opportunities for novel interventions. In this brief summary, some of the potential targets in ovarian cancer are discussed, including the HER kinases, heat shock protein, the 26S proteasome, and the angiogenesis pathway. The opportunities to change the treatment of ovarian cancer will require creative clinical trial design but the next decade promises to be filled the therapeutic advances for patients with ovarian cancer.

Angiogenesis Inhibitors↗

Platelet septin complexes form rings and associate with the microtubular network.

BACKGROUND: Septins are important effectors in molecular mechanisms involving membrane partitioning. To date, a growing repertoire of septins in mammals includes 13 different proteins (SEPT1 to SEPT13) that can be classified into four distinct categories based on sequence similarity. AIM: In this study, we document the human platelet septin, SEPT5, as part of a complex composed of multiple septin proteins. RESULTS: Biochemical and immunofluorescent data place the majority of these complexes in the platelet periphery as part of the platelet circumferential band copurifying with the platelet microtubule coil and tubulin. The presence of a prominent platelet septin ring in resting platelets appears to be left intact in the activated platelet, as a similar ring structure is observed following platelet spreading on fibrinogen. The ablation of SEPT5 in the knock-out mouse model had previously been reported to result in a platelet phenotype with aggregation using subthreshold levels of agonist. Speculation on the role of SEPT5 in the platelet-release reaction suggested that SEPT5 regulates platelet function by association with platelet storage granules. We now report that the absence of SEPT5 results in increased ATP release from stimulated platelets. CONCLUSION: These studies document the presence of platelet septin complexes and validate the importance of septins for platelet physiology.

Adenosine Triphosphate↗

Host cell and malarial targets for docetaxel (Taxotere) during the erythrocytic development of Plasmodium falciparum.

The microtubular stabilizing agent docetaxel (Taxotere) is known to inhibit the intraerythrocytic development of Plasmodium falciparum. To investigate the mechanism(s) of inhibition, we analyzed the structural organization of the mitotic spindle by immunofluorescence and electron microscopy. When 30 microM docetaxel was applied for five hours on ring forms, alterations in the mitotic spindles leading to abnormal nuclear divisions were observed. At the trophozoite- and schizont-stage, docetaxel pulses prevent mitosis by stabilizing microtubular structures associated with the mitotic apparatus, giving abnormal spindles. However, this inhibition did not interfere with parasite DNA synthesis indicating the absence of a checkpoint that couples exit from mitosis with proper spindle assembly as observed in higher eukaryotic cells. In parallel, intraerythrocytic concentration of docetaxel was measured in parasitized erythrocytes, after incubation of cells with 3H-docetaxel for five hours. It was found to be 14-fold increased at the ring-stage of infected erythrocytes compared to normal ones, 170-fold increased at the trophozoite-stage and 1,500-fold increased at the schizont-stage. Our data show that, even though the overall intracellular concentration of docetaxel is low in docetaxel-pulsed rings, the agent might be sufficient to disturb the spindle organization. However, the existence of targets for docetaxel other than mitotic spindle microtubules, i.e. erythrocyte membrane components could interfere with mitotic spindle formation.

Animals↗

Effects of tubulin assembly inhibitors on cell division in prokaryotes in vivo.

The bacterial cell division protein FtsZ is a structural analogue of tubulin. Bacterial mutants in which the ftsZ gene is inactivated are unable to divide. Numerous inhibitors of tubulin assembly are known, some of which are used as fungicides. The strong structural homology between FtsZ and tubulin raises the possibility that some of these inhibitors could affect bacterial cell division. Here we report that the tubulin assembly inhibitors thiabendazole and 2-methylbenzimidazole cause cell elongation in Escherichia coli and cyanobacteria.

Bacterial Proteins↗

Antagonistic forces generated by cytoplasmic dynein and myosin-II during growth cone turning and axonal retraction.

Cytoplasmic dynein transports short microtubules down the axon in part by pushing against the actin cytoskeleton. Recent studies have suggested that comparable dynein-driven forces may impinge upon the longer microtubules within the axon. Here, we examined a potential role for these forces on axonal retraction and growth cone turning in neurons partially depleted of dynein heavy chain (DHC) by small interfering RNA. While DHC-depleted axons grew at normal rates, they retracted far more robustly in response to donors of nitric oxide than control axons, and their growth cones failed to efficiently turn in response to substrate borders. Live cell imaging of dynamic microtubule tips showed that microtubules in DHC-depleted growth cones were largely confined to the central zone, with very few extending into filopodia. Even under conditions of suppressed microtubule dynamics, DHC depletion impaired the capacity of microtubules to advance into the peripheral zone of the growth cone, indicating a direct role for dynein-driven forces on the distribution of the microtubules. These effects were all reversed by inhibition of myosin-II forces, which are known to underlie the retrograde flow of actin in the growth cone and the contractility of the cortical actin during axonal retraction. Our results are consistent with a model whereby dynein-driven forces enable microtubules to overcome myosin-II-driven forces, both in the axonal shaft and within the growth cone. These dynein-driven forces oppose the tendency of the axon to retract and permit microtubules to advance into the peripheral zone of the growth cone so that they can invade filopodia.

Actins↗

Dietary antioxidant curcumin inhibits microtubule assembly through tubulin binding.

Curcumin, a component of turmeric, has potent antitumor activity against several tumor types. However, its molecular target and mechanism of antiproliferative activity are not clear. Here, we identified curcumin as a novel antimicrotubule agent. We have examined the effects of curcumin on cellular microtubules and on reconstituted microtubules in vitro. Curcumin inhibited HeLa and MCF-7 cell proliferation in a concentration-dependent manner with IC(50) of 13.8 +/- 0.7 microm and 12 +/- 0.6 microm, respectively. At higher inhibitory concentrations (> 10 microm), curcumin induced significant depolymerization of interphase microtubules and mitotic spindle microtubules of HeLa and MCF-7 cells. However, at low inhibitory concentrations there were minimal effects on cellular microtubules. It disrupted microtubule assembly in vitro, reduced GTPase activity, and induced tubulin aggregation. Curcumin bound to tubulin at a single site with a dissociation constant of 2.4 +/- 0.4 microm and the binding of curcumin to tubulin induced conformational changes in tubulin. Colchicine and podophyllotoxin partly inhibited the binding of curcumin to tubulin, while vinblastine had no effect on the curcumin-tubulin interactions. The data together suggested that curcumin may inhibit cancer cells proliferation by perturbing microtubule assembly dynamics and may be used to develop efficacious curcumin analogues for cancer chemotherapy.

Antioxidants↗

Polycystin-2 cation channel function in the human syncytiotrophoblast is regulated by microtubular structures.

Polycystin-2 (PC2), encoded by PKD2, which is one of the genes whose mutations cause polycystic kidney disease, is abundantly produced in the apical domain of the syncytiotrophoblast (hST) of term human placenta. PC2, a TRP-type (TRPP2) non-selective cation channel, is present in primary cilia of renal epithelial cells, a microtubule-based ancillary structure with sensory function. The hST has abundant cytoskeletal structures, and actin filament dynamics regulate PC2 channel function in this epithelium. However, it is expected that the apical hST excludes microtubular structures. Here, we demonstrated by Western blot and immunocytochemical analyses that hST apical vesicles indeed contain microtubule structural components, including tubulin isoforms, acetylated alpha-tubulin, and the kinesin motor proteins KIF3A and KIF3B. PC2 and tubulin were substantially colocalized in hST vesicles. Treatment of hST vesicles with either the microtubular disrupter colchicine (15 microM) or the microtubular stabilizer paclitaxel (taxol, 15 microM) resulted in distinct patterns of microtubular re-organization and PC2 redistribution. We also observed that changes in microtubular dynamics regulate PC2 channel function. Addition of colchicine rapidly inhibited PC2 channel activity in lipid-bilayer reconstituted hST membranes. Addition of either tubulin and GTP, or taxol, however, stimulated PC2 channel activity in control hST membranes. Interestingly, we found that the kinesin motor protein KIF3A was capable of increasing PC2 channel activity in hST. We believe that the data are the first to provide a direct demonstration of a microtubular interaction with PC2 in the hST. This interaction thus plays an important regulatory role in the control of ion transport in the human placenta.

Cations↗

Microtubule-destabilizing agents induce focal adhesion structure disorganization and anoikis in cancer cells.

Microtubule disruption provokes cytoskeleton and cell adhesion changes whose importance for apoptosis induction remains unclear. The present study focuses on the functional and the molecular adhesion kinetics that are induced by microtubule disruption-mediated apoptosis. We showed that antimicrotubules induce a biphasic sequence of adhesion response that precedes the onset of apoptosis and focal adhesion kinase hydrolysis. Antimicrotubules first induced an increase of the cellular adhesion paralleled by the raise of focal adhesion sites and actin contractility, which was followed by a sharp decrease of cell adhesion and disorganization of focal adhesion and actin stress fibers. The latter sequence of events ends by cell rounding, detachment from the extracellular matrix, and cell death. Microtubule-disrupting agents induced a sustained paxillin phosphorylation, before the activation of apoptosis, that requires the prior activation of extracellular signal-regulated kinase and p38 but not c-Jun NH(2)-terminal kinase. Interestingly, integrin-linked kinase overexpression rescued the antimicrotubule-mediated loss of cell viability. Altogether, these results propound that antimicrotubule agents induce anoikis through the loss of focal adhesion structure integrity.

Animals↗

RPR112378 and RPR115781: two representatives of a new family of microtubule assembly inhibitors.

A screening program aimed at the discovery of new antimicrotubule agents yielded RPR112378 and RPR115781, two natural compounds extracted from the Indian plant Ottelia alismoides. We report their isolation, structural determination, and mechanisms of action. RPR112378 is an efficient inhibitor of tubulin polymerization (IC(50) = 1.2 microM) and is able to disassemble preformed microtubules. Regarding tubulin activity, RPR115781 is 5-fold less active than RPR112378. Tubulin-RPR112378 complexes, when isolated by gel filtration, were able to block further tubulin addition to growing microtubules, a mechanism that accounts for the substoichiometric effect of the drug. RPR112378 was found to prevent colchicine binding but not vinblastine binding to tubulin. Although colchicine binding is known to induce an increase of tubulin GTPase activity, no such increase was observed with RPR112378. We show that RPR112378 is a highly cytotoxic compound and that RPR115781 is 10, 000-fold less active as an inhibitor of KB cell growth. Part of the cytotoxicity of RPR112378 is probably caused by a reaction of addition with sulfhydryl groups, an observation that has not been made with RPR115781. In conclusion, these molecules represent a new class of inhibitors of microtubule assembly with potential therapeutic value.

Antineoplastic Agents, Phytogenic↗

A steroid derivative with paclitaxel-like effects on tubulin polymerization.

The endogenous estrogen metabolite 2-methoxyestradiol has modest antimitotic activity that may result from a weak interaction at the colchicine binding site of tubulin, but it nevertheless has in vivo antitumor activity. Synthetic efforts to improve activity led to compounds that increased inhibitory effects on cell growth, tubulin polymerization, and binding of colchicine to tubulin. This earlier work was directed at modifications in the steroid A ring, which is probably analogous to the colchicine tropolonic C ring. One of the most active analogs prepared was 2-ethoxyestradiol (2EE). We report here that different modifications in the steroid B ring of 2EE yield compounds with two apparently distinct modes of action. Simple expansion of the B ring to seven members resulted in a compound comparable to 2EE in its ability to inhibit tubulin polymerization and colchicine binding to tubulin. Acetylation of the hydroxyl groups in this analog and in 2EE essentially abolished these inhibitory properties. The introduction of a ketone functionality at C6, together with acetylation of the hydroxyls at positions 3 and 17, produced a compound with activity similar to that of paclitaxel, in that the agent enhanced tubulin polymerization into polymers that were partially stable at 0 degrees C. The acetyl group at C17, but not that at C3, was essential for this paclitaxel-like activity.

2-Methoxyestradiol↗

Involvement of nuclear factor kappaB in c-Myc induction by tubulin polymerization inhibitors.

We showed previously that microtubule disassembly by vinblastine induces the proto-oncogene c-myc in epithelial mammary HBL100 cells. In this study, we demonstrate that vinblastine treatment in these cells, in contrast to what was observed with the colon adenocarcinoma cell line HT29-D4, activated the transcription factor NFkappaB, which has been involved in c-myc regulation. The microtubule disassembly also induced IkappaB degradation. Using transient transfection analysis, we show that the trans-activation of c-myc by vinblastine was decreased when NFkappaB binding sites on c-myc promoter were mutated. Additionally, we demonstrate that microtubule dissolution trans-activated a thymidine kinase-CAT construct containing an NFkappaB binding site at -1180 to -1080 bp relative to the P1 promoter. Thus, vinblastine up-regulates the enhancer activity of the NFkappaB binding site. These results suggest that microtubule disassembly induced by vinblastine can trans-activate the c-myc oncogene through NFkappaB. Taking into consideration the paradoxical roles of both c-myc and NFkappaB in proliferation or apoptosis, this data reveals the complex action mechanism of this microtubule interfering agent.

Antineoplastic Agents, Phytogenic↗

Salvinal, a novel microtubule inhibitor isolated from Salvia miltiorrhizae Bunge (Danshen), with antimitotic activity in multidrug-sensitive and -resistant human tumor cells.

Aqueous extracts of Salvia miltiorrhizae Bunge have been extensively used in the treatment of cardiovascular disorders and cancer in Asia. Recently, a compound, 5-(3-hydroxypropyl)-7-methoxy-2-(3'-methoxy-4'-hydroxyphenyl)-3-benzo[b]furancarbaldehyde (salvinal), isolated from this plant showed inhibitory activity against tumor cell growth and induced apoptosis in human cancer cells. In the present study, we investigated the cytotoxic effect and mechanisms of action of salvinal in human cancer cell lines. Salvinal caused inhibition of cell growth (IC50 range, 4-17 microM) in a variety of human cancer cell lines. Flow cytometry analysis showed that salvinal treatment resulted in a concentration-dependent accumulation of cells in the G(2)/M phase. We observed, using Hoechst 33258 dye staining, that salvinal blocked the cell cycle in mitosis. In vitro and in vivo examinations showed that salvinal inhibited tubulin polymerization in a concentration-dependent manner. Immunocytochemical studies demonstrated that salvinal treatment caused the changes of cellular microtubule network, similar to the effect of colchicine. In addition, salvinal treatment resulted in upregulation of cyclin B1 levels, activation of Cdc2 kinase, and Cdc25c phosphorylation. Furthermore, elevation of levels of MPM-2 phosphoepitopes in salvinal-treated cells in a concentration-dependent manner was also observed. Similar to the effect of other antitubulin agent, hyperphosphorylation of Bcl-2, induction of DNA fragmentation and activation of caspase-3 activity occurred in salvinal-treated cells. In particular, salvinal exhibited similar inhibitory activity against parental KB, P-glycoprotein-overexpressing KB vin10 and KB taxol-50 cells, and multidrug resistance-associated protein (MRP)-expressing etoposide-resistant KB 7D cells. Taken together, our data demonstrate that salvinal inhibits tubulin polymerization, arrests cell cycle at mitosis, and induces apoptosis. Notably, Salvinal is a poor substrate for transport by P-glycoprotein and MRP. Salvinal may be useful in the treatment of human cancers, particularly in patients with drug resistance.

Aldehydes↗

Laulimalide and paclitaxel: a comparison of their effects on tubulin assembly and their synergistic action when present simultaneously.

Previous work has shown that laulimalide, a sponge-derived natural product, resembles paclitaxel in enhancing tubulin assembly and in its effects on cellular microtubules. The two compounds, however, seem to have distinct binding sites on tubulin polymer. Nearly equimolar amounts of tubulin, laulimalide, and paclitaxel are recovered from microtubules formed with both drugs. In the present study, we searched for differences between laulimalide and paclitaxel in their interactions with tubulin polymer. Laulimalide was compared with paclitaxel and epothilone A, a natural product that competes with paclitaxel in binding to microtubules, for assembly properties at different temperatures and for effects of GTP and microtubule-associated proteins on assembly. Although minor differences were observed among the three drugs, their overall effects were highly similar, except that aberrant assembly products were observed more frequently with paclitaxel and that the polymers formed with laulimalide and epothilone A were more stable at 0 degrees C. The most dramatic difference observed between laulimalide and epothilone A was that only laulimalide was able to enhance assembly synergistically with paclitaxel, as would be predicted if the two drugs bound at different sites in polymer. Because stoichiometric amounts of laulimalide and paclitaxel can cause extensive tubulin assembly, maximum synergy was observed at lower temperatures under reaction conditions in which each drug alone is relatively inactive. Laulimalide-induced assembly, like paclitaxel-induced assembly, was inhibited by drugs that inhibit tubulin assembly by binding at either the colchicine- or vinblastine-binding site. When radiolabeled GTP is present in a reaction mixture with either laulimalide or paclitaxel, nucleotide hydrolysis occurs with incorporation of radiolabeled GDP into polymer.

Animals↗

Inhibition of leishmanias but not host macrophages by the antitubulin herbicide trifluralin.

The dinitroaniline herbicide trifluralin (alpha, alpha, alpha-trifluoro-2,6-dinitro-N, N-dipropyl-p-toluidine), at micromolar concentrations, selectively inhibited both proliferation and differentiation of the parasitic protozoan Leishmania mexicana amazonensis. In vitro, radioactive trifluralin showed specific binding to leishmania tubulin but not to mammalian tubulin. Because herbicides such as trifluralin are economical and are considered safe for man and domesticated animals, they may serve as useful sources of potential antiparasitic agents.

Animals↗

Activities of several benzimidazoles and tubulin inhibitors against Giardia spp. in vitro.

Previous studies in our laboratory have shown that albendazole is effective against Giardia spp. in vitro and in vivo, prompting an investigation of the effects of several related benzimidazoles (BZs) on the viability of this protozoan parasite. A range of BZs was tested, and their effects were compared with those of a number of microtubule inhibitors. The effects produced by the two types of drugs were markedly similar, namely, trophozoite detachment and distortion of morphology and general structure, indicating a potential antimicrotubule mode of action for BZs. Mebendazole, albendazole, and fenbendazole proved to be among the most effective BZs tested, exhibiting apparent irreversibility. Nocodazole, oxfendazole, and albendazole sulfoxide, among others, produced transient inhibitions only. Further studies are required to evaluate all available BZs and other antigiardial agents to ensure the development of the most effective and safest antigiardial agent possible.

Albendazole↗

Challenging the role of microtubules in Tobacco mosaic virus movement by drug treatments is disputable.

The movement protein (MP) of Tobacco mosaic virus interacts with microtubules during infection. Although this interaction is correlated with the function of MP in the cell-to-cell transport of viral RNA, a direct role of microtubules in the movement process was recently challenged by studies involving the treatment of plants with inhibitors of microtubule polymerization. Here, we report evidence suggesting that such treatments may not efficiently disrupt all microtubules. Thus, results obtained from studies using microtubule inhibitors may have to remain open to interpretation with regard to the involvement of microtubules in viral RNA trafficking.

Arabidopsis↗