Imatinib mesylate (Gleevec, Novartis, Basel, Switzerland) is a small-molecule tyrosine kinase inhibitor with activity against ABL, BCR-ABL, c-KIT, and PDGFR alpha. Several clinical trials have evaluated the efficacy and safety of imatinib in patients with ovarian carcinoma who have persistent or recurrent disease following front-line platinum/taxane based chemotherapy. However, there is limited pre-clinical and clinical data on the molecular targets and action of imatinib in ovarian cancer.
Human ovarian cancer cells (A2780) were treated with imatinib mesylate for either 6 or 24 h. We employed a 2D (two-dimensional) gel electrophoresis and mass spectrometry-based proteomics approach to identify protein expression patterns and signaling pathways that were altered in response to imatinib. Cells were analyzed for PDGFR alpha and AKT expression, which were then correlated with imatinib sensitivity.
Using 2D gel electrophoresis of overlapping pH ranges from pH 4 to 11, about 4,000 protein spots could be analyzed reproducibly. Proteins whose levels changed between twofold to 30 fold were grouped according to whether changes were in the same direction at both time points of treatment with respect to the control, or changed their levels only at one of the time points.
Differentially regulated proteins following imatinib treatment of A2780 cells involved the regulation of actin cytoskeleton, metabolic pathways, cell cycle, cell proliferation, apoptosis, cell junctions, and signal transduction. Thus, exposure of cells to imatinib produces complex changes in the cell that require further investigation.
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"KAI1 (CD82), a tumor metastasis suppressor gene, has wide-spectrum roles in targeting tumor metastasis [11,12] . Many studies have confirmed that the KAI1/CD82 gene inhibits metastasis in various types of cancers such as endometrial, pancreatic, bladder, breast, ovarian, cervical, lung, hepatic, colorectal and gastric cancer131415 . The main purpose of this study is to determine the effect of various imatinib concentrations on cell viability and metastasis through modulation of KAI1/CD82 gene expression in breast cancer MCF-7 cell line. "
[Show abstract][Hide abstract]ABSTRACT: Objective: To evaluate the effect of imatinib mesylate on cell viability, anti cancer effect through modulation of KAI1/CD82 gene expression in breast cancer MCF-7 cell line. Methods: The effects of imatinib mesylate on cell viability in MCF-7 cell line were assessed using MTT assay and IC50 value was determined. GAPDH and KAI1/CD82 were selected as reference and target genes, respectively. Quantitative real time PCR technique was applied for investigation of KAI1/CD82 gene expression in human breast cancer MCF-7 cells. Subsequently, the quantity of KAI1 compared to GAPDH gene expressions were analyzed using the formula; 2-δδCt. Results: Imatinib was showed to have a dose-dependent inhibitory effect on the viability of MCF-7 cells. CD82/. GAPDH gene expression ratios were 1.322 ± 0.030 (P > 0.05), 2.052 ± 0.200 (P < 0.05), 2.151 ± 0.270 (P < 0.05) for 10, 20 and 40 μmol/L of imatinib concentrations. Conclusions: Based on the present data, imatinib mesylate might modulate metastasis by up-regulating KAI1/CD82 gene expression in human breast MCF-7 cancer cell line.
Full-text · Article · Dec 2015 · Asian Pacific Journal of Tropical Biomedicine
"Therefore, c-KIT could be a perfecttherapeutic target of a tyrosine kinase inhibitor as imatinib. Furthermore, Patel and his colleagues demonstrated that imatinib mesylate is involved in complex cellular processes, including metabolic pathways, cell cycle, cell proliferation, apoptosis, and signal transduction through mass spectrometry-based proteomics method in human ovarian cancer cell line A2780
[Show abstract][Hide abstract]ABSTRACT: In 2013 there will be an estimated 22,240 new diagnoses and 14,030 deaths from ovarian cancer in the United States. Despite the improved surgical approach and the novel active drugs that are available today in clinical practice, about 80% of women presenting with late-stage disease have a 5-year survival rate of only 30%. In the last years a growing scientific knowledge about the molecular pathways involved in ovarian carcinogenesis has led to the discovery and evaluation of several novel molecular targeted agents, with the aim to test alternative models of treatment in order to overcome the clinical problem of resistance. Cancer stem cells tend to be more resistant to chemotherapeutic agents and radiation than more differentiated cellular subtypes from the same tissue. In this context the study of ovarian cancer stem cells is taking on an increasingly important strategic role, mostly for the potential therapeutic application in the next future. In our review, we focused our attention on the molecular characteristics of epithelial ovarian cancer stem cells, in particular on possible targets to hit with targeted therapies.
Full-text · Article · Aug 2013 · Journal of Experimental & Clinical Cancer Research
[Show abstract][Hide abstract]ABSTRACT: Identification of the potential gene expression profiles of epithelial ovarian cancer and the arrival of newly targeted therapies have advanced the strategies used for treatment of this disease. This review focuses on the design of ongoing and planned clinical trials and offers a synopsis of the English-language literature for preclinical and clinical targeted therapies for epithelial ovarian cancer. Among many targeted agents, a promising, novel class of targeted drugs for special patient populations expected to improve the effectiveness of current therapy include inhibitors of angiogenesis, poly (ADP ribose) polymerase (PARP) and DNA repair mechanisms. Inhibition of PARP or homologous recombination (HR) repair mediated by Chk1 (checkpoint kinase 1) would selectively sensitize p53 mutation, BRCAness phenotype (serous type ovarian cancer) or HNF (hepatocyte nuclear factor)-1β-overexpressing tumor cells (clear cell type ovarian cancer) to chemotherapeutic agents. The therapeutic response is likely to be limited to a targeted patient, but not to the broad population. This review discusses some of the key current developments and existing challenges.