Disruption of Microtubules Sensitizes the DNA Damage-induced Apoptosis Through Inhibiting Nuclear Factor kappaB (NF-kappaB) DNA-binding Activity

The massive reorganization of microtubule network involves in transcriptional regulation of several genes by controlling transcriptional factor, nuclear factor-kappa B (NF-kappaB) activity. The exact molecular mechanism by which microtubule rearrangement leads to NF-kappaB activation largely remains to be identified. However microtubule disrupting agents may possibly act in synergy or antagonism against apoptotic cell death in response to conventional chemotherapy targeting DNA damage such as adriamycin or comptothecin in cancer cells. Interestingly pretreatment of microtubule disrupting agents (colchicine, vinblastine and nocodazole) was observed to lead to paradoxical suppression of DNA damage-induced NF-kappaB binding activity, even though these could enhance NF-kappaB signaling in the absence of other stimuli. Moreover this suppressed NF-kappaB binding activity subsequently resulted in synergic apoptotic response, as evident by the combination with Adr and low doses of microtubule disrupting agents was able to potentiate the cytotoxic action through caspase-dependent pathway. Taken together, these results suggested that inhibition of microtubule network chemosensitizes the cancer cells to die by apoptosis through suppressing NF-kappaB DNA binding activity. Therefore, our study provided a possible anti-cancer mechanism of microtubule disrupting agent to overcome resistance against to chemotherapy such as DNA damaging agent.

Suppression of multidrug resistance via inhibition of heat shock factor by quercetin in MDR cells

MDR1 promoter has been shown to contain heat shock elements (HSE), and it has been reported that FM3A/M and P388/M MDR cells show a constitutively activated heat shock factor (HSF), suggesting that HSF might be an important target for reversing the multidrug resistance. Therefore, it was examined whether quercetin, which has been shown to interfere with the formation of the complex between HSE and HSF, and to downregulate the level of HSF1, can sensitize MDR cells against anticancer drugs by inhibition of HSF DNA-binding activity. In this study, quercetin appeared to inhibit the constitutive HSF DNA-binding activity and the sodium arsenite-induced HSF DNA-binding activity in the MDR cells. The basal and sodium arsenite-induced MDRCAT activities were remarkably suppressed by the treatment of quercetin. These results were well consistent with the finding that the treatment of quercetin decreased the expression level of P-gp, MDR1 gene product, in dose-dependent manner, and markedly increased the sensitivity of MDR cells to vincristine or vinblastine. These results suggest that quercetin can decrease the expression of P-gp via inhibition of HSF DNA-binding activity, and might be useful as a chemosensitizer in MDR cells.

Light and electron microscopic observation on rat molar periodontal ligament after intraperitoneal injection of vinblastine

The effect of intraperitoneal injection of Vinblastine sulfate on rat periodontal ligament was studied. Cells still synthetize collagen after 2 hours of the injection with evidence of loss of extracellular collagen fibers orientation. Tubular lysosome could not be detected after 2 hours with formation of lysosomal clusters in the cell center. After 4 hours of administration, evidences of cell degeneration were observed. The present study has shown that Vinblastine produces effect on fibroblasts as early as two hours after injection

Efecto de la vinblastina sobre la secreción biliar y la ultraestructura hepática en la rata / Effect of vinblastine on bile secretion and hepatic ultrastructure in rats

Se estudió la influencia de la vinblastina, droga que causa inhbición de la polimerización de la tubulina a microtúbulos, sobre la secreción biliar y la ultraestructura hepática en ratas. La vinblastina fue administrada endovenosamente a la dosis de 2mg por 100g p.c., 2 horas antes de efectuar el estudio. Se observó lo seguiente: 1) el flujo biliar basal y la secreción basal de ácidos biliares no fueron modificados: 2) el flujo biliar y la secreción de ácidos biliares disminuyeron después de una sobrecarga de ácidos biliares, y 3) el examen de microscopía electrónica de los hepatocitos, en los animales tratados con vinblastina, reveló la desaparición casi completa de los microtúbulos, un aumento en el número y tamaño de las vesículas de lipoproteína de muy baja densidad, y la configuración anormal de mitocondrias caracterizada por un aumento de la densidad matrical y figuras de partición. Estos resultados apoyan la hipótesis sobre la partición de los microtúbulos en los mecanismos de secreción biliar, además de demostrar una acción de la vinblastina sobre la estructura mitocondrial

Role of 5-HT on increased permeability of blood-brain barrier under heat stress.

Exposure of young rats (9-10 wks) to chronic summer heat (36 degrees C) or acute heat (38 degrees C 4hr) increased the BBB permeability to Evans blue albumin complex (MW 68,000) and 131I-sodium (MW 154) in different brain regions which correlated well with the increased level of 5-HT in plasma and brain. This increased permeability of BBB and the increased 5-HT level were prevented by pretreatment with p-CPA, indomethacin and diazepam. Cyproheptadine and vinblastine pretreatment however, prevented only the increased permeability of BBB, the plasma and brain 5-HT level continued to remain high. These results indicate a probable role of 5-HT as one of the factors leading to the increased permeability of BBB in young rats following heat stress.