gsk343 has been researched along with 3-deazaneplanocin* in 3 studies
3 other study(ies) available for gsk343 and 3-deazaneplanocin
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EZH2 inhibitors reverse resistance to gefitinib in primary EGFR wild-type lung cancer cells.
Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. In traditional anti-cancer therapy, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) have been proven to be beneficial for patients with EGFR mutations. However, patients with EGFR wild-type NSCLC were usually not respond to EGFR-TKIs. Enhancer of zeste homolog 2 (EZH2) is a key molecular in the PRC2 complex and plays an important role in epigenetic regulation and is overexpressed in variant tumors. EZH2 inhibitors have been reported to sensitize variant tumor cells to anticancer drugs. This study aimed to investigate whether the EZH2 inhibitors, GSK343 and DZNep when combined with gefitinib can reverse EGFR-TKIs resistance in EGFR wild-type NSCLC cells.. The RNA-sequencing data of patients with NSCLC [502 patients with lung squamous cell carcinoma, including 49 paracancerous lung tissues and 513 patients with lung adenocarcinoma (LUAD), including 59 paracancerous lung tissues] from the Cancer Genome Atlas (TCGA), were analyzed for EZH2 expression. EZH2 expression was verified in 40 NSCLC tissue cancer samples and their corresponding paracancerous tissues from our institute (TJMUGH) via RT-PCR. A549 and H1299 cells treated with siRNA or EZH2 inhibitors were subjected to cell viability and apoptosis analyses as well to EGFR pathway proteins expression analyses via western blotting.. EZH2 was upregulated in human NSCLC tissues and correlated with poor prognosis in patients with LUAD based on data from both TCGA and TJMUGH. Both GSK343 and DZNep sensitized EGFR wild-type LUAD cells (A549 and H1299) to gefitinib and suppressed cell viability and proliferation in vitro by downregulating the phosphorylation of EGFR and AKT and by inducing cell apoptosis. Co-administration of EZH2 inhibitors (GSK343 or DZNep) with gefitinib exerted a stronger inhibitory effect on tumor activity, cell proliferation and cell migration than single drug administration in vitro and in vivo.. These data suggest that the combination of EZH2 inhibitors with EGFR-TKIs may be an effective method for treating NSCLC-patients with EGFR-wild type, who do not want to undergo traditional treatment with chemotherapy. Topics: Adenosine; Adult; Aged; Animals; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; Cell Movement; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Enhancer of Zeste Homolog 2 Protein; Female; Gefitinib; Gene Expression Regulation, Neoplastic; Genes, erbB-1; Humans; Indazoles; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Neoplasm Invasiveness; Neoplasm Proteins; Protein Kinase Inhibitors; Pyridones; RNA Interference; RNA, Neoplasm; RNA, Small Interfering; Signal Transduction | 2020 |
Investigation of EZH2 pathways for novel epigenetic treatment strategies in oropharyngeal cancer.
In recent decades, the incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been rising worldwide as a result of increasing oncogenic human papillomavirus (HPV) infections in the oropharynx. EZH2 is an epigenetic regulatory protein associated with tumor aggressiveness and negative survival outcomes in several human cancers. We aimed to determine the role of EZH2 as a potential therapeutic epigenetic target in HPV-positive and negative OPSCC.. The expression of EZH2 was measured by immunohistochemistry (IHC) and droplet digital PCR (ddPCR) in 2 HPV-positive and 2 HPV-negative cell lines. The cell lines were then cultured and treated with one of 3 EZH2 epigenetic inhibitors (3-deazaneplanocin A, GSK-343 and EPZ005687) or DMSO (control). Following 2, 4 and 7 days of treatment, cells were analyzed and compared by gene expression, cell survival and proliferation assays.. EZH2 targeting resulted in greater inhibition of growth and survival in HPV-positive compared to HPV-negative cells lines. The expression profile of genes important in OPSCC also differed according to HPV-positivity for Ki67, CCND1, MET and PTEN/PIK3CA, but remained unchanged for EGFR, CDKN2A and p53.. Inhibition of EZH2 has anti-tumorigenic effects on OPSCC cells in culture that is more pronounced in HPV-positive cell lines. EZH2 is a promising epigenetic target for the treatment of OPSCC. Topics: Adenosine; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cell Survival; Enhancer of Zeste Homolog 2 Protein; Epigenomics; Humans; Immunohistochemistry; Indazoles; Oropharyngeal Neoplasms; Papillomavirus Infections; Polymerase Chain Reaction; Pyridones; Tumor Cells, Cultured | 2016 |
S-Adenosyl-L-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells.
The enhancer of zeste homolog 2 (EZH2) has emerged as a novel anticancer target. Various EZH2 inhibitors have been developed in recent years. Among these, 3-deazaneplanocin A (DZNep) is known to deplete EZH2 protein expression through an indirect pathway. In contrast, GSK343 directly inhibits enzyme activity through an S-adenosyl-L-methionine-competitive pathway. Therefore, we proposed that DZNep and GSK343 may exert differential effects against cancer cells. In this study, we found that GSK343 but not DZNep induced autophagic cell death of cancer cells. Inhibition of EZH2 expression was not required for GSK343-induced autophagy. In addition, GSK343 enhanced the anticancer activity of a multikinase inhibitor, sorafenib, in human hepatocellular carcinoma cells. Our results show that GSK343 is a more potent anticancer agent than DZNep, and for the first time, we show that it acts as an autophagy inducer. Topics: Adenosine; Antineoplastic Combined Chemotherapy Protocols; Autophagy; Cell Line, Tumor; Cell Survival; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Gene Knockdown Techniques; Hep G2 Cells; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Indazoles; Niacinamide; Phenylurea Compounds; Polycomb Repressive Complex 2; Pyridones; S-Adenosylmethionine; Sorafenib | 2015 |