ABSTRACT
The epithelial to mesenchymal transition (EMT) is a key step during embryonic morphogenesis and plays an important role in drug resistance and metastasis in diverse solid tumors. We previously reported that 48 h treatment of anti-cancer drug doxorubicin could induce EMT in human gastric cancer BGC-823 cells. However, the long term effects of this transient drug treatment were unknown. In this study we found that after 48 h treatment with 0.1 µg/ml doxorubicin, most cells died during next week, while a minor population of cells survived and formed colonies. We propagated the surviving cells in drug free medium and found that these long term cultured drug survival cells (abbreviated as ltDSCs) retained a mesenchymal-like cell morphology, and expressed high levels of EMT-related molecules such as vimentin, twist and ß-catenin. The expression of chromatin reprogramming factors, Oct4 and c-myc, were also higher in ltDSCs than parental cells. We further demonstrated that the protein level of p300 was upregulated in ltDSCs, and inhibition of p300 by siRNA suppressed the expression of vimentin. Moreover, the ltDSCs had higher colony forming ability and were more drug resistant when compared to parental cells. Our results suggested that an epigenetic mechanism is involved in the EMT of ltDSCs.
Subject(s)
Doxorubicin/pharmacology , Epigenesis, Genetic/genetics , Epithelial-Mesenchymal Transition/drug effects , Stomach Neoplasms/pathology , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , E1A-Associated p300 Protein/biosynthesis , E1A-Associated p300 Protein/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Nuclear Proteins/biosynthesis , Octamer Transcription Factor-3/biosynthesis , Proto-Oncogene Proteins c-myc/biosynthesis , RNA Interference , RNA, Small Interfering , Stomach Neoplasms/drug therapy , Twist-Related Protein 1/biosynthesis , Vimentin/biosynthesis , beta Catenin/biosynthesisABSTRACT
To synthesize and evaluate antimicrobial activity of novel heterocyclic compounds, the corresponding title aroyl ureas have been synthesized by the reaction of 2-amino-5-(3-pyridyl)-1, 3, 4-thiadiazole with aroyl isocyanates. Their antimicrobial activities in vitro were tested by disk diffusion methods and broth microdilution according to M-27A protocol recommended by NCCLS. Twelve new compounds were obtained, and their structures were confirmed by MS, IR, 1H NMR and elemental analysis. The biological screening tests showed that most of the compounds have some antifungal activities in vitro. Aroyl ureas incorporating pyridyl thiadiazole ring may be developed as novel antifungal candidate drugs and are worthwhile to be further studied.
