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1.
Nutr Cancer ; 62(8): 1025-35, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21058190

RESUMO

Quercetin is a flavonoid with anticancer properties. In this study, we examined the effects of quercetin on cell cycle, viability, and proliferation of cancer cells, either singly or in combination with the microtubule-targeting drugs taxol and nocodazole. Although quercetin induced cell death in a dose-dependent manner, 12.5-50 µM quercetin inhibited the activity of both taxol and nocodazole to induce G2/M arrest in various cell lines. Quercetin also partially restored drug-induced loss in viability of treated cells for up to 72 h. This antagonism of microtubule-targeting drugs was accompanied by a delay in cell cycle progression and inhibition of the buildup of cyclin-B1 at the microtubule organizing center of treated cells. However, quercetin did not inhibit the microtubule targeting of taxol or nocodazole. Despite the short-term protection of cells by quercetin, colony formation and clonogenicity of HCT116 cells were still suppressed by quercetin or quercetin-taxol combination. The status of cell adherence to growth matrix was critical in determining the sensitivity of HCT116 cells to quercetin. We conclude that although long-term exposure of cancer cells to quercetin may prevent cell proliferation and survival, the interference of quercetin with cell cycle progression diminishes the efficacy of microtubule-targeting drugs to arrest cells at G2/M.


Assuntos
Antineoplásicos Fitogênicos/metabolismo , Ciclo Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Nocodazol/antagonistas & inibidores , Paclitaxel/antagonistas & inibidores , Quercetina/metabolismo , Moduladores de Tubulina/antagonistas & inibidores , Adesão Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina B1/metabolismo , Interações Alimento-Droga , Fase G2/efeitos dos fármacos , Humanos , Microtúbulos/efeitos dos fármacos , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/prevenção & controle , Nocodazol/farmacologia , Concentração Osmolar , Paclitaxel/farmacologia , Fatores de Tempo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
2.
Curr Biol ; 20(21): 1881-9, 2010 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-20951045

RESUMO

BACKGROUND: During cytokinesis, regulatory signals are presumed to emanate from the mitotic spindle. However, what these signals are and how they lead to the spatiotemporal changes in the cortex structure, mechanics, and regional contractility are not well understood in any system. RESULTS: To investigate pathways that link the microtubule network to the cortical changes that promote cytokinesis, we used chemical genetics in Dictyostelium to identify genetic suppressors of nocodazole, a microtubule depolymerizer. We identified 14-3-3 and found that it is enriched in the cortex, helps maintain steady-state microtubule length, contributes to normal cortical tension, modulates actin wave formation, and controls the symmetry and kinetics of cleavage furrow contractility during cytokinesis. Furthermore, 14-3-3 acts downstream of a Rac small GTPase (RacE), associates with myosin II heavy chain, and is needed to promote myosin II bipolar thick filament remodeling. CONCLUSIONS: 14-3-3 connects microtubules, Rac, and myosin II to control several aspects of cortical dynamics, mechanics, and cytokinesis cell shape change. Furthermore, 14-3-3 interacts directly with myosin II heavy chain to promote bipolar thick filament remodeling and distribution. Overall, 14-3-3 appears to integrate several critical cytoskeletal elements that drive two important processes-cytokinesis cell shape change and cell mechanics.


Assuntos
Proteínas 14-3-3/fisiologia , Citocinese/fisiologia , Dictyostelium/citologia , Microtúbulos/metabolismo , Miosina Tipo II/metabolismo , Nocodazol/farmacologia , Proteínas rac de Ligação ao GTP/metabolismo , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Citocinese/genética , Dictyostelium/genética , Dictyostelium/ultraestrutura , Regulação para Baixo , Biblioteca Gênica , Microtúbulos/efeitos dos fármacos , Microtúbulos/ultraestrutura , Miosina Tipo II/fisiologia , Nocodazol/antagonistas & inibidores , Proteínas rac de Ligação ao GTP/fisiologia
3.
Am J Physiol Lung Cell Mol Physiol ; 287(1): L86-93, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15003930

RESUMO

Cross talk between the actin cytoskeleton and the microtubule (MT) network plays a critical role in regulation of endothelial permeability. We have previously demonstrated that MT disruption by nocodazole results in increases in MLC phosphorylation, actomyosin contraction, cell retraction, and paracellular gap formation, cardinal features of endothelial barrier dysfunction (Verin AD, Birukova A, Wang P, Liu F, Becker P, Birukov K, and Garcia JG. Am J Physiol Lung Cell Mol Physiol 281: L565-L574, 2001; Birukova AA, Smurova K, Birukov KG, Usatyuk P, Liu F, Kaibuchi K, Ricks-Cord A, Natarajan V, Alieva A, Garcia JG, and Verin AD. J Cell Physiol. In press.). Although activation of PKA opposes barrier-disrupting effects of edemagenic agents on confluent EC monolayers, information about the molecular mechanisms of PKA-mediated EC barrier protection is limited. Our results suggest that MT disassembly alters neither intracellular cAMP levels nor PKA enzymatic activity; however, elevation of cAMP levels and PKA activation by either cholera toxin or forskolin dramatically attenuates the decline in transendothelial electrical resistance induced by nocodazole in human pulmonary EC. Barrier-protective effects of PKA on EC were associated with PKA-mediated inhibition of nocodazole-induced stress fiber formation, Rho activation, phosphorylation of myosin phosphatase regulatory subunit at Thr696, and decreased MLC phosphorylation. In addition, forskolin pretreatment attenuated MT disassembly induced by nocodazole. These results suggest a critical role for PKA activity in stabilization of MT cytoskeleton and provide a novel mechanism for cAMP-mediated regulation of Rho-induced actin cytoskeletal remodeling, actomyosin contraction, and EC barrier dysfunction induced by MT disassembly.


Assuntos
Permeabilidade Capilar/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Endotélio Vascular/metabolismo , Microtúbulos/fisiologia , Actinas/fisiologia , Proteínas de Fase Aguda/metabolismo , Animais , Bovinos , Células Cultivadas , Colforsina/farmacologia , AMP Cíclico/metabolismo , Endotélio Vascular/citologia , Ativação Enzimática/fisiologia , Humanos , Isoenzimas/metabolismo , Microtúbulos/efeitos dos fármacos , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Nocodazol/antagonistas & inibidores , Nocodazol/farmacologia , Fosforilação , Artéria Pulmonar
4.
Biosci Biotechnol Biochem ; 67(1): 139-50, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12619685

RESUMO

Mepanipyrim inhibited retrograde Golgi-to-ER trafficking induced by brefeldin A (BFA), nordihydroguaiaretic acid, clofibrate, and arachidonyltrifluoromethyl ketone in NRK and other types of cells, but did not inhibit anterograde trafficking of Golgi-resident proteins translocated to ER by BFA and newly synthesized VSV-G. However, mepanipyrim did not block the TGN38 dispersion induced by any of these compounds. Mepanipyrim acted on the Golgi, and swollen vesicular Golgi structures were formed and similar structures accumulated during rebuilding of the Golgi after BFA removal. These actions of mepanipyrim were readily reversed after its removal. Mepanipyrim did not stabilize microtubules, but prevented nocodazole-induced fragmentation and dispersion of the Golgi. These results suggest that the mepanipyrim-sensitive molecules participated in stabilizing the Golgi and its anchoring in the perinuclear region, and equally importantly, that the novel action of mepanipyrim may be used as a pharmacological tool for investigating membrane transport, Golgi membrane dynamics, and differentiation of the Golgi from TGN.


Assuntos
Fungicidas Industriais/farmacologia , Pirimidinas/farmacologia , Rede trans-Golgi/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Western Blotting , Brefeldina A/antagonistas & inibidores , Brefeldina A/farmacologia , Proteínas de Transporte/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Corantes Fluorescentes , Humanos , Masoprocol/farmacologia , Camundongos , Microscopia de Fluorescência , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Nocodazol/antagonistas & inibidores , Nocodazol/farmacologia , Oligossacarídeos/metabolismo , Rede trans-Golgi/metabolismo
5.
Biosci Biotechnol Biochem ; 65(6): 1369-78, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11471737

RESUMO

PDMP (D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol) and PPMP (D,L-threo-1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol), inhibitors of glucosylceramide synthesis, blocked brefeldin A (BFA)- and nordihydroguaiaretic acid-induced dispersal of the Golgi and trans Golgi network, and Golgi-derived vesicles were retained in the juxtanuclear region. PDMP and PPMP did not stabilize microtubules but blocked nocodazole-induced extensive fragmentation and dispersal of the Golgi, and large Golgi vesicles were retained in the juxtanuclear region. PPMP is a stronger inhibitor of glucosylceramide synthesis than PDMP, but PDMP showed a stronger activity against BFA-induced retrograde membrane flow. However, PPMP showed a stronger activity for Golgi disruption and inhibition of anterograde trafficking from the endoplasmic reticulum, and rebuilding of the Golgi architecture. Cumulatively, these results suggest that sphingolipid metabolism is implicated in maintenance of the Golgi architecture and anterograde membrane flow from the endoplasmic reticulum but not in Golgi dispersal induced by BFA.


Assuntos
Membrana Celular/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glucosilceramidas/antagonistas & inibidores , Glucosilceramidas/biossíntese , Complexo de Golgi/efeitos dos fármacos , Morfolinas/farmacologia , Esfingolipídeos/metabolismo , Esfingolipídeos/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/antagonistas & inibidores , Antineoplásicos/farmacologia , Brefeldina A/antagonistas & inibidores , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/ultraestrutura , Retículo Endoplasmático/ultraestrutura , Corantes Fluorescentes , Complexo de Golgi/ultraestrutura , Inibidores de Lipoxigenase/farmacologia , Masoprocol/farmacologia , Microscopia de Fluorescência , Microtúbulos/efeitos dos fármacos , Microtúbulos/ultraestrutura , Nocodazol/antagonistas & inibidores , Nocodazol/farmacologia , Ratos
6.
J Cell Sci ; 100 ( Pt 2): 299-310, 1991 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-1757489

RESUMO

The protein kinase inhibitor 2-aminopurine (2-AP) inhibits a subset of mitotic events in BHK cells. In the presence of the drug, these cells form a bipolar spindle in mitosis, but chromatin fails to generate functioning chromosomes. Cells in 2-AP progress through a partial mitosis, in which there is no observable metaphase, anaphase or telophase events. After 12 h of exposure to 2-AP the chromatin in mitotic cells fails to condense into discrete chromosomes, and is displaced by the spindle to form 'binucleate' cells and cells containing abnormally shaped nuclei in the subsequent interphase. Other mitotic modifications of nuclei, such as nucleolar and nuclear lamina disassembly, occur normally. Centromeres in these nuclei do not become engaged in the spindle, but instead show either no association or a lateral arrangement around the spindle. Cells treated with 2-AP are not arrested in mitosis. Therefore, mitotic exit is not inhibited by the failure of these cells to progress through the latter stages of mitosis. Further, nocodazole-arrested cells quickly exit mitotic arrest when 2-AP is added. We conclude that 2-AP interferes with a specific subset of mitotic events, and that it allows cells to overcome check-points that require spindle function for mitotic progression.


Assuntos
2-Aminopurina/farmacologia , Mitose/efeitos dos fármacos , Anáfase , Animais , Proteína Quinase CDC2/metabolismo , Núcleo Celular/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Cricetinae , Metáfase , Microscopia de Fluorescência , Modelos Biológicos , Nocodazol/antagonistas & inibidores , Fuso Acromático/efeitos dos fármacos , Telófase
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