RESUMO
Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Since differentiation can attenuate or halt the growth of tumor cells, an image-based phenotypic screening was performed to find out drugs inducing morphological differentiation of GBMs. Bexarotene, a selective retinoid X receptor agonist, showed strong inhibition of neurospheroidal colony formation and migration of cultured primary GBM cells. Bexarotene treatment reduced nestin expression, while significantly increasing glial fibrillary acidic protein (GFAP) expression. The effect of bexarotene on gene expression profile was compared with the activity of all-trans retinoic acid (ATRA), a well-known differentiation inducer. Both drugs largely altered the gene expression pattern into a tumor-ameliorating direction. These drugs increased the gene expression levels of Krüppel-like factor 9 (KLF9), regulator of G-protein signaling 4 (RGS4), growth differentiation factor 15 (GDF15), angiopoietin-like protein 4 (ANGPTL4), and lowered the level of chemokine receptor type 4 (CXCR4). However, transglutaminase 2 (TG2) induction, an adverse effect of ATRA, was much weaker in bexarotene treated primary GBM cells. Consistently, the TG2 enzymatic activity was negligibly affected by bexarotene treatment. It is important to control TG2 overexpression since its upregulation is correlated with tumor transformation and drug resistance. Bexarotene also showed in vivo tumoricidal effects in a GBM xenograft mouse model. Therefore, we suggest bexarotene as a more beneficial differentiation agent than ATRA for GBM.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Proteínas de Ligação ao GTP/genética , Glioblastoma/tratamento farmacológico , Tetra-Hidronaftalenos/administração & dosagem , Transglutaminases/genética , Proteína 4 Semelhante a Angiopoietina , Angiopoietinas/biossíntese , Animais , Bexaroteno , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proteínas de Ligação ao GTP/biossíntese , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Glioblastoma/patologia , Fator 15 de Diferenciação de Crescimento/biossíntese , Humanos , Fatores de Transcrição Kruppel-Like/biossíntese , Camundongos , Proteína 2 Glutamina gama-Glutamiltransferase , Proteínas RGS/biossíntese , Receptores CXCR4/biossíntese , Receptores X de Retinoides/agonistas , Transdução de Sinais/efeitos dos fármacos , Transglutaminases/biossíntese , Tretinoína/administração & dosagem , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We examined whether (-)-nicotine infusion can affect kainic acid (KA)-induced neurotoxicity in rats. Although treatment with a single nicotine infusion (0.5 or 1.0 microg/side, i.c.v.) failed to attenuate KA-induced neurotoxicity, repeated nicotine infusions (1.0 microg/side/day for 10 days) attenuated the seizures, the severe loss of cells in hippocampal regions CA1 and CA3, the increase in activator protein (AP)-1 DNA binding activity, and mortality after KA administration. alpha-Bungarotoxin and mecamylamine blocked the neuroprotective effects of nicotine. These results suggest that repeated nicotine treatment provides alpha7 nicotinic acetylcholine receptor-mediated neuroprotection against KA toxicity.
Assuntos
Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Nicotina/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Convulsões/prevenção & controle , Fator de Transcrição AP-1/metabolismo , Animais , Bungarotoxinas/farmacologia , DNA/metabolismo , Di-Hidro-beta-Eritroidina/farmacologia , Hipocampo/patologia , Injeções Intraventriculares , Ácido Caínico , Excitação Neurológica , Masculino , Mecamilamina/farmacologia , Nicotina/administração & dosagem , Antagonistas Nicotínicos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/metabolismo , Convulsões/induzido quimicamente , Convulsões/mortalidade , Receptor Nicotínico de Acetilcolina alfa7RESUMO
Aralia elata Seemann is an edible mountain vegetable in Korea containing saponin, alkaloid, palmitic acid, linoleic acid, methyl eicosanoate and hexacosol, and is known to manifest an effect on cardiac infarction, gastric ulcer, colitis, and enervation. This study has examined the effects of Aralia elata Seemann ethanol extract on antioxidant enzyme systems and lipid metabolism in rats along with benzo(a)pyrene (B(a)P) administration. Rats were divided into four groups: control (C), an extract fed group (CE), a B(a)P fed group (CB), and a B(a)P and extract fed group (CBE). The ethanol extracts of Aralia elata Seemann (50 mg/kg body weight) were fed to the rats for 4 weeks by stomach tubing. Extract administration increased the antioxidant activities of glutathione sulfur transferase (GST). Total superoxide dismutase (SOD) and Cu,Zn-SOD activities were stimulated. Catalase activities were increased by 50% with extract feeding. Cu,Zn-SOD was greatly enhanced from 0.10 unit to 0.18 unit and catalase activity also was increased. Serum alpha-tocopherol was markedly increased by the extracts. The ethanol fraction of Aralia elata Seemann decreased total serum cholesterol. However, serum HDL-cholesterol was increased by 35% (p<0.05). The results indicate that Aralia elata Seemann exerts antioxidant and strong hypocholesterolemic and hypolipidemic effects in vivo with the administration of B(a)P.