RESUMO
Synthetic phosphate-derived functional groups are important for controlling the function of bioactive molecules inâ vivo. Herein we describe the development of a new type of biocompatible phosphate analog, a fluorophosphoramidate (FPA) functional group that has characteristic P-F and P-N bonds. We found that FPA with a primary amino group was relatively unstable in aqueous solution and was converted to a monophosphate, while FPA with a secondary amino group was stable. Furthermore, by improving the molecular design of FPA, we developed a reaction in which a secondary amino group is converted to a primary amino group in the intracellular environment and clarified that the FPA group functions as a phosphate prodrug of nucleoside. Various FPA-gemcitabine derivatives were synthesized and their toxicity to cancer cells were evaluated. One of the FPA-gemcitabine derivatives showed superior toxicity compared with gemcitabine and its ProTide prodrug, which methodology is widely used in various nucleoside analogs, including anti-cancer and anti-virus drugs.
Assuntos
Neoplasias , Pró-Fármacos , Antivirais/farmacologia , Humanos , Fosfatos , Pró-Fármacos/química , Pró-Fármacos/farmacologiaRESUMO
OBJECTIVE: To observe the effect of luteolin on the proliferation and expression of OPCML in breast cancer cell line MDA-MB-231. METHODS: Cultured MDA-MB-231 cells were treated with luteolin at the concentrations of 5, 10 and 20 µmol/L for 24 or 48 h. MTT assay was used to detect cell proliferation and flow cytometry was used to detect the cell apoptosis. The expressions of OPCML mRNA and protein were detected using real-time quantitative PCR and Western blotting, respectively. OPCML gene methylation in the promoter region was detected using methylation-specific PCR (MSP), and the activity of methylase in the cells was analyzed. RESULTS: MTT assay showed that treatment with luteolin at 5, 10 and 20 µmol/L for 24 h concentration-dependently decreased the viability of MDA-MB-231 cells (P < 0.05). Flow cytometry also showed that luteolin at different concentrations could induce apoptosis of MDA-MB-231 cells (P < 0.05). Luteolin dose-dependently induced the expression of OPCML mRNA and protein in MDA-MB-231 cells (P < 0.05), down-regulated the methylation status in the promoter region of OPCML gene, up-regulated the level of non-methylated OPCML, and reduced the activity of methylase in the cells (P < 0.05). CONCLUSIONS: Luteolin inhibits the proliferation of MDA-MB-231 breast cancer cells probably by upregulating OPCML expression and its demethylation.
Assuntos
Neoplasias da Mama , Proliferação de Células , Apoptose , Moléculas de Adesão Celular , Linhagem Celular Tumoral , Proteínas Ligadas por GPI , Humanos , LuteolinaRESUMO
AIM: To explore the prognostic value of clusterin (CLU) in hepatocellular carcinoma (HCC) patients treated with oxaliplatin (OXA). METHODS: Relative expression of plasma CLU mRNA was examined via fluorescence quantitative real-time PCR (qRT-PCR), and CLU protein level in tissue samples was detected through immunohistochemistry. Chi-square test was used to analyze the relationship between CLU mRNA expression and clinical features of HCC patients treated with OXA. Kaplan-Meier method was performed to assess overall survival for the patients, and prognostic value of CLU in HCC patients was estimated via Cox regression analysis. RESULTS: CLU expression in plasma and tissue specimens was significantly higher among HCC patients than in non-malignant controls (P < 0.001 for both). Moreover, elevated CLU mRNA was closely related to tumor stage, lymph node metastasis and response to OXA (P < 0.05). HCC patients with high CLU expression showed poor response to OXA. In addition, low CLU levels predicted long overall survival time among the study subjects (20.8 vs. 36.6 months, P < 0.001). CLU was an independent prognostic indicator for HCC patients treated with OXA (HR = 2.587, 95%CI = 1.749-3.828, P < 0.001). CONCLUSION: CLU may be a novel prognostic marker for HCC patients treated with OXA.