RESUMO
Astroglioma is the most common primary tumor in the central nervous system without effective treatment strategies. Temozolomide (TMZ) is a chemotherapeutic drug to treat astroglioma but exhibits low potency and has side effects. Therefore, there is an urgent need to develop new compounds to treat astroglioma. Dalbergia sissoo Roxb was the source of Dalbergia odorifera in traditional Chinese medicine (TCM) and has been clinically used as an anti-tumor medicine. 4-Methoxydalbergione (4MOD) is purified from Dalbergia sissoo Roxb., and shows an inhibitory effect on osteosarcoma, but its effects on astroglioma have not been reported. Here, we evaluate its anti-astroglioma effects on both in vitro and in vivo models. In cultured astroglioma U87 cells, 4MOD inhibited cell proliferation and induced cell apoptosis in a time- and concentration-dependent manner. Compared with TMZ, 4MOD exhibited a tenfold greater potency of anti-astroglioma effects. 4MOD effectively stalled the cell cycle in G2 phase. Transcriptome sequencing (RNA-seq) showed that 4MOD upregulated 158 genes and downregulated 204 genes that are mainly enriched in cell membrane, cell division, cell cycle, p53, TNF, and MAPK signaling pathways, which may underlie its anti-tumor mechanisms. In a nude mouse xenograft model transplanted with U87 cells, 10 mg/kg 4MOD slowed down tumor growth rate, while at 30 mg/kg dose, it reduced tumor size. Collectively, this study demonstrates that 4MOD is a potent native compound that remarkably inhibits U87 astroglioma growth in both in vitro and in vivo models.
Assuntos
Astrocitoma/tratamento farmacológico , Astrocitoma/metabolismo , Benzoquinonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Astrocitoma/genética , Astrocitoma/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dalbergia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Expressão Gênica , Xenoenxertos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos NusRESUMO
In this study, one immortalized human normal prostatic epithelial cell line (BPH) and four human prostate cancer cell lines (LNCaP, 22Rv1, PC-3, and DU-145) were treated with Ganoderma Lucidum triterpenoids (GLT) at different doses and for different time periods. Cell viability, apoptosis, and cell cycle were analyzed using flow cytometry and chemical assays. Gene expression and binding to DNA were assessed using real-time PCR and Western blotting. It was found that GLT dose-dependently inhibited prostate cancer cell growth through induction of apoptosis and cell cycle arrest at G1 phase. GLT-induced apoptosis was due to activation of Caspases-9 and -3 and turning on the downstream apoptotic events. GLT-induced cell cycle arrest (mainly G1 arrest) was due to up-regulation of p21 expression at the early time and down-regulation of cyclin-dependent kinase 4 (CDK4) and E2F1 expression at the late time. These findings demonstrate that GLT suppresses prostate cancer cell growth by inducing growth arrest and apoptosis, which might suggest that GLT or Ganoderma Lucidum could be used as a potential therapeutic drug for prostate cancer.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Próstata/efeitos dos fármacos , Reishi/química , Triterpenos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/genética , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Relação Dose-Resposta a Droga , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Humanos , Masculino , Nucleossomos/efeitos dos fármacos , Nucleossomos/metabolismo , Nucleossomos/patologia , Extratos Vegetais/química , Próstata/metabolismo , Próstata/patologia , Transdução de Sinais , Triterpenos/isolamento & purificaçãoRESUMO
Beta-amyloid peptide (Aß), a major protein component of senile plaques associated with Alzheimer's disease (AD), is also directly neurotoxic. Mitigation of Aß-induced neurotoxicity is thus a possible therapeutic approach to delay or prevent onset and progression of AD. This study evaluated the protective effect of Bajijiasu (ß- D-fructofuranosyl (2-2) ß- D-fructofuranosyl), a dimeric fructose isolated from the Chinese herb Radix Morinda officinalis, on Aß-induced neurotoxicity in pheochromocytoma (PC12) cells. Bajijiasu alone had no endogenous neurotoxicity up to 200 µM. Brief pretreatment with 10-40 µM Bajijiasu (2 h) significantly reversed the reduction in cell viability induced by subsequent 24 h exposure to Aß25-35 (21 µM) as measured by MTT and LDH assays, and reduced Aß25-35-induced apoptosis as indicated by reduced annexin V-EGFP staining. Bajijiasu also decreased the accumulation of intracellular reactive oxygen species and the lipid peroxidation product malondialdehyde in PC12 cells, upregulated expression of glutathione reductase and superoxide dismutase, prevented depolarization of the mitochondrial membrane potential (Ψm), and blocked Aß25-35-induced increases in [Ca(2+)] i . Furthermore, Bajijiasu reversed Aß25-35-induced changes in the expression levels of p21, CDK4, E2F1, Bax, NF-κB p65, and caspase-3. Bajijiasu is neuroprotective against Aß25-35-induced neurotoxicity in PC12 cells, likely by protecting against oxidative stress and ensuing apoptosis.