ABSTRACT
Resistance to epidermal growth factor receptor (EGFR) inhibitors is of primary concern in the treatment of nonsmallcell lung cancer (NSCLC) with EGFR mutations. To investigate the effects of matrine on H1975 cells and to examine a novel, potential treatment option for NSCLC, the present study measured cell viability, apoptotic rate, interleukin 6 (IL6) expression and activation of the janus kinase (JAK) 1/signal transducer and activator of transcription (STAT)3 signaling pathway in cells treated with or without matrine, in the presence or absence of afatinib. The results demonstrated that matrine treatment inhibited cell growth, decreased Bcell lymphoma 2 (Bcl2) expression and induced apoptosis. Matrine treatment additionally decreased the mRNA and protein levels of IL6 and inhibited activation of the JAK1/STAT3 signaling pathway in H1975 cells in a dosedependent manner. H1975 cells treated with IL6 small interfering RNA exhibited a decrease in Bcl2 expression levels and cell viability. Treatment with a combination of matrine and afatinib demonstrated increased inhibitory effects on the growth rate of H1975 cells. The findings of the present study suggested that matrine treatment decreases IL6 expression, inhibits activation of the JAK1/STAT3 signaling pathway, reduces the expression levels of Bcl2 and inhibits cell growth. Furthermore, matrine treatment was demonstrated to increase the inhibitory effects of afatinib on H1975 cells with the T790M EGFR mutation.
Subject(s)
Alkaloids/pharmacology , Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Quinolizines/pharmacology , Signal Transduction/drug effects , Afatinib , Apoptosis/drug effects , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Humans , Interleukin-6/metabolism , Janus Kinase 1/metabolism , Lung Neoplasms/metabolism , STAT3 Transcription Factor/metabolism , MatrinesABSTRACT
In this study, a novel amphiphilic block copolymer biomaterial - poly (ethylene glycol)-poly (caprolactone) (PEG-PCL), was used to entrap norcantharidin (NCTD), taking advantage of self-assembly theory. Dialysis and volatilization dialysis were used to prepare copolymer micelles. Drug-loaded micelles were compared with blank micelles in terms of their particle diameter, morphology and IR spectral characteristics. The results revealed that there was no significant difference in respect of morphology and IR spectrum, but particle size differed. Drug-loaded micelles had a smaller particle size than blank micelles. Three important factors influencing particle size, the drug loading content (LC) and the drug entrapment efficiency (EE) of the NCTD-loaded micelles, were studied. The results indicated that the method of preparation and the type of organic solvent had a significant influence on the size of the micelles. LC and EE were greatly affected by the ratio of NCTD to copolymer. In vitro release of NCTD from the conjugate micelles showed that its release rate depended on the pH of the phosphate buffer solution (PBS). The amount released was higher at lower pH than under neutral conditions. In vitro antitumor activity of the NCTD conjugate against human hepatoma (HepG2) cell line and human lung cancer (A549) cell line was evaluated by the MTT method. Micelles loaded with NCTD demonstrated greater and more satisfactory cell viability inhibition than the free drug. In vivo antitumor activity of drug-loaded micelles was investigated in mice bearing S180 mouse sarcoma. NCTD-loaded micelles displayed tumor inhibition effects, better than the free drug. As a new drug delivery system, copolymer micelles present many advantages including easy formulation, good water solubility, low toxicity and high treatment efficacy, and show great potential as carriers of hydrophobic drugs.
