ABSTRACT
The epidermal growth factor receptor (EGFR)tyrosine kinase inhibitor (TKI), gefitinib, is an effective therapeutic drug used in the treatment of nonsmall cell lung cancers (NSCLCs) harboring EGFR mutations. However, acquired resistance significantly limits the efficacy of EGFRTKIs and consequently, the current chemotherapeutic strategies for NSCLCs. It is, therefore, necessary to overcome this resistance. In the present study, the anticancer potential of natural extracts of Coptis chinensis (ECC) against gefitinibresistant (GR) NSCLC cells were investigated in vitro and in vivo. ECC inhibited the viability, migration and invasion, and effectively induced the apoptosis of GR cells. These effects were associated with the suppression of EGFR/AKT signaling and the expression of antiapoptotic proteins, Mcl1 and Bcl2, which were overexpressed in GR NSCLC cells. Combination treatment with ECC and gefitinib enhanced the sensitivity of GR cells to gefitinib in vitro, but not in vivo. However, ECC increased the survival of individual zebrafish without affecting the anticancer effect to cancer cells in vivo, which indicated a specific cytotoxic effect of ECC on cancer cells, but not on normal cells; this is an important property for the development of novel anticancer drugs. On the whole, the findings of the present study indicate the potential of ECC for use in the treatment of NSCLC, particularly in combination with EGFRTKI therapy, in EGFRTKIresistant cancers.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Coptis/chemistry , Drug Resistance, Neoplasm/drug effects , Gefitinib/administration & dosage , Lung Neoplasms/drug therapy , Phytochemicals/administration & dosage , Animals , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Cell Movement/drug effects , Cell Survival/drug effects , Drug Synergism , Gefitinib/pharmacology , Gene Expression Regulation, Leukemic/drug effects , Humans , Lung Neoplasms/metabolism , Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors , Phytochemicals/chemistry , Phytochemicals/pharmacology , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Xenograft Model Antitumor Assays , ZebrafishABSTRACT
Hepatitis B viruses (HBV) specifically target the liver, where they efficiently infect quiescent hepatocytes. Thus, HBV virus has potential to be used as vectors for liver-directed gene transfer. We constructed a new HBV-based vector system. It is composed of transfer vector for transferring a foreign gene, green fluorescence protein (GFP) gene, and a helper vector. When the transfer vector and the helper vector were cotransfected into HepG2 cells, the recombinant HBV (rHBV) particles were generated by trans-complementation between two vectors. The rHBV particles carrying the foreign gene were identified by the Southern blot assay. To test gene delivery and the transduction of the rHBV, we infected primary human hepatocytes and immortalized, HepG2 cells with rHBV in vitro. The results using fluorescence microscopy confirmed that the inserted GFP gene was successfully transferred and expressed both in primary human hepatocytes and HepG2 cells.
