Search results for "Kinase inhibitor"
showing 10 items of 414 documents
Epigenetic changes and nuclear factor-κB activation, but not microRNA-224, downregulate Raf-1 kinase inhibitor protein in triple-negative breast canc…
2015
Raf-1 kinase inhibitor protein (RKIP) is a tumor suppressor and metastasis inhibitor, which enhances drug-induced apoptosis of cancer cells. Downregulation of RKIP may be significant in the biology of highly aggressive and drug-resistant tumors, for example triple-negative breast cancers (TNBCs). Potential causes for the low levels of RKIP expressed by SUM 159 TNBC cells were investigated in the present study. Bisulphite modification, methylation specific-polymerase chain reaction (PCR) and a TransAM NF-κB assay were performed and the results suggested that various mechanisms, including methylation of the gene promoter, histone deacetylation and nuclear factor-κB (NF-κB) activation, but not…
Intratumoral Heterogeneity in EGFR-Mutant NSCLC Results in Divergent Resistance Mechanisms in Response to EGFR Tyrosine Kinase Inhibition
2015
Abstract Non–small cell lung cancers (NSCLC) that have developed resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI), including gefitinib and erlotinib, are clinically linked to an epithelial-to-mesenchymal transition (EMT) phenotype. Here, we examined whether modulating EMT maintains the responsiveness of EGFR-mutated NSCLCs to EGFR TKI therapy. Using human NSCLC cell lines harboring mutated EGFR and a transgenic mouse model of lung cancer driven by mutant EGFR (EGFR-Del19-T790M), we demonstrate that EGFR inhibition induces TGFβ secretion followed by SMAD pathway activation, an event that promotes EMT. Chronic exposure of EGFR-mutated NSCLC cells to TGFβ was sufficient to ind…
Shikonin and its derivatives inhibit the epidermal growth factor receptor signaling and synergistically kill glioblastoma cells in combination with e…
2015
Overexpression and mutation of the epidermal growth factor receptor (EGFR) gene play a causal role in tumorigenesis and resistance to treatment of glioblastoma (GBM). EGFR inhibitors such as erlotinib are currently used for the treatment of GBM; however, their efficacy has been limited due to drug resistance. New treatment strategies are therefore urgently needed. Shikonin, a natural naphthoquinone, induces both apoptosis and necroptosis in human glioma cells, but the effectiveness of erlotinib-shikonin combination treatment as well as the underlying molecular mechanisms is unknown yet. In this study, we investigated erlotinib in combination with shikonin and 14 shikonin derivatives in pare…
The role of second-line tyrosine kinase inhibitor monotherapy in EGFR wild-type advanced non-small-cell lung cancer patients: Findings from a retrosp…
2015
e19030 Background: Second-line treatment for advanced non-small-cell lung cancer (aNSCLC) patients includes monotherapy with a third generation cytotoxic drug (CT) or with the tyrosine kinase inhib...
Rad51 and BRCA2 - New Molecular Targets for Sensitizing Glioma Cells to Alkylating Anticancer Drugs
2011
First line chemotherapeutics for brain tumors (malignant gliomas) are alkylating agents such as temozolomide and nimustine. Despite growing knowledge of how these agents work, patients suffering from this malignancy still face a dismal prognosis. Alkylating agents target DNA, forming the killing lesion O(6)-alkylguanine, which is converted into DNA double-strand breaks (DSBs) that trigger apoptosis. Here we assessed whether inhibiting repair of DSBs by homologous recombination (HR) or non-homologous end joining (NHEJ) is a reasonable strategy for sensitizing glioma cells to alkylating agents. For down-regulation of HR in glioma cells, we used an interference RNA (iRNA) approach targeting Ra…
Aspidin PB, a phloroglucinol derivative, induces apoptosis in human hepatocarcinoma HepG2 cells by modulating PI3K/Akt/GSK3β pathway.
2012
Aspidin PB, a phloroglucinol derivative isolated from Dryopteris fragrans (L.) Schott, has been previously reported to exert high biological activities. In the present study, we analyzed the apoptotic mechanisms of aspidin PB on human hepatoma cell line, HepG2. Initially, aspidin PB was shown to inhibit the growth of HepG2 cells in a time and dose-dependent manner. After treatment with aspidin PB for 72 h, 48 h and 24 h using MTT assay, the IC(50) values were 10.59 μM, 20.86 μM and 46.59 μM, respectively. Aspidin PB was capable to induce apoptosis, as measured by mitochondrial membrane potential (ΔΨm), acridine orange (AO) staining and propidium iodide (PI)/annexin V-FITC double staining. T…
Analysis of Possible Mechanisms Accounting for Raf-1 Kinase Inhibitor Protein Downregulation in Hepatocellular Carcinoma
2012
Abstract Raf-1 kinase inhibitor protein (RKIP) is a tumor and metastasis suppressor that promotes drug-induced apoptosis in cancer cells. It is frequently downregulated, both at the mRNA and protein level, in hepatocellular carcinoma (HCC), but the mechanisms leading to this reduction are obscure. We sequenced the whole RKIP gene in three human HCC cell lines (HA22T/VGH, HepG2, and Hep3B), and in five clinical HCC samples, but could not find any gene variant that might account for their low RKIP levels. We also examined whether gene methylation may be responsible for the altered RKIP expression. No methylation of the RKIP gene was found in the tumor samples, while among the cell lines only …
From molecular mechanisms to clinical management of antineoplastic drug-induced cardiovascular toxicity: A translational overview
2019
Significance: Antineoplastic therapies have significantly improved the prognosis of oncology patients. However, these treatments can bring to a higher incidence of side-effects, including the worrying cardiovascular toxicity (CTX). Recent Advances: Substantial evidence indicates multiple mechanisms of CTX, with redox mechanisms playing a key role. Recent data singled out mitochondria as key targets for antineoplastic drug-induced CTX; understanding the underlying mechanisms is, therefore, crucial for effective cardioprotection, without compromising the efficacy of anti-cancer treatments. Critical Issues: CTX can occur within a few days or many years after treatment. Type I CTX is associated…
Timely recognition of cardiovascular toxicity by anticancer agents: a common objective of the pharmacologist, oncologist and cardiologist.
2011
Both conventional and new anticancer drugs can frequently cause adverse cardiovascular effects, which can span from subclinical abnormalities to serious life-threatening and sometimes fatal events. This review examines the principal basic and clinical elements that may be of profit to identify, prevent and treat such toxicities. Clearly, the accomplishment of such objectives requires the strong commitment and cooperation of different professional figures including, but not limited to, pharmacologists, oncologists and cardiologists. The aspect of anticancer drug cardiotoxicity seems to be somehow underestimated, mainly due to inadequate reporting of adverse reactions from oncology drugs in t…
Kinetic and thermodynamic insights into interaction of erlotinib with epidermal growth factor receptor: Surface plasmon resonance and molecular docki…
2020
Abstract Epidermal growth factor receptor (EGFR) plays an important role in cell proliferation at non-small cell lung cancer (NSCLC). Therefore, targeted therapy of cancer via this kind of receptor is highly interested. Small molecule drugs such as erlotinib and gefitinib inhibit EGFR tyrosine kinase and thus suppress cell proliferation. At this paper, erlotinib interaction with EGFR on the cell surface was studied via surface plasmon resonance (SPR) and molecular docking methods. Kinetic parameters indicated that erlotinib affinity toward EGFR was increased through increment of temperature. The thermodynamic analysis showed that van der Waals and hydrogen binding forces play a major role i…