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Editor’s Choice : EGCG Suppresses Melanoma Tumor Angiogenesis and Growth without Affecting Angiogenesis and VEGF Expression in the Heart and Skeletal Muscles in Mice
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Abstract: Melanoma is a highly malignant cancer with a potent capacity to metastasize distantly and has a higher mortality. There is no effective therapy for high risk melanoma patients to prevent relapse or distant metastasis. Therefore effective chemoprevention strategies are needed. The present study mainly evaluates the effects of EGCG on melanoma angiogenesis, growth, and capillary density (CD) in the heart and skeletal muscles of mice. 5 x 10^5 B16F10 cells were inoculated into the right proximal dorsal of the back in the eight week old male mice (n=12). Then, 6 mice received EGCG at 50–100 mg/kg/d in drinking water for 4 weeks and 6 control mice received drinking water only. Tumor size was monitored using dial calipers. At the end of the experiment, blood samples, tumors, hearts, and limb muscles were collected and measured for VEGF expression using ELISA and capillary density (CD) using CD31 immunohistochemistry. Compared to the control, EGCG treatment significantly reduced tumor weight (2.9±0.5 vs. 5.9±1.1 g; P<0.01; n=6), melanoma CD (117±9 vs. 167±23; P<0.01), and melanoma VEGF expression (32±1.5 vs. 42±2 pg/mg; P < 0.01), respectively. Also EGCG had no effects on body weight, heart weight, angiogenesis or VEGF expression in the heart and skeletal muscle of mice. EGCG (20-50 µg/ml) significantly inhibited the proliferation, migration, VEGF expression, and the activation of HIF-1α and NFκB in cultured B16F10 cells, respectively. These findings support the hypothesis that EGCG, a major green tea polyphenol, directly targets tumor cells and tumor vasculature, thereby inhibiting tumor growth, proliferation, migration, and angiogenesis of melanoma, and that the down-regulation of VEGF expression by EGCG is associated with the inhibition of HIF-1α and NFκB activation. EGCG has great potential as a chemopreventive agent because it has no effect on angiogenesis in normal tissue and has low toxicity. Keywords: Melanoma, angiogenesis, proliferation, migration, EGCG, green tea polyphenols,VEGF,HIF-1α, NFκB, and capillary density in the heart.Download Full Article |
Editor’s Choice : Factors Influencing Percentage Yield of Side Population Isolated in Ovarian Cancer Cell LineSK-OV-3
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Abstract: Isolation of side population (SP) cells has been recognized as a useful technique for the isolation and identification of hematopoietic stem cells or cancer stem cells (CSCs). Thus the yield and purity of isolated SP cells would have a profound influence on the research outcomes in these two important areas. Hoechst 33342 exclusion assay technique has been used for the identification of SP cells. However, diverse Hoechst staining protocols giving different SP yields even from the same tissue type or same cell line have been reported in different laboratories. In this study we systematically investigated the underlying factors influencing the SP yield using Hoechst dye staining and a robust platform of flow cytometric analysis of the human ovarian cancer cell line SK-OV-3. Our study revealed that SP yield was not only affected by the Hoechst 33342 concentration, staining cell density, staining cell viability, staining duration, staining medium, flow cytometric setting and SP gating strategy, but was also affected by the cell passage number in SK-OV-3. This is the first systematic study on the factors affecting SP yield in adherent cells that mimic many solid tumour tissues. Our results provide important technical guidelines to help ensure reproducible and comparable results in SP and CSCs study. Keywords: Side population (SP), SK-OV-3, cancer stem cells (CSCs), flow cytometry (FCM), Hoechst 33342.Download Full Article |
Editor’s Choice : Targeting Cancer Stem Cells with Defined Compounds and Drugs
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Abstract: Cancer stem cells (CSCs) are a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of cancer cells that comprise the tumor. CSCs possess numerous intrinsic mechanisms of resistance to chemotherapeutic drugs, novel tumor-targeted drugs and radiation therapy, allowing them to survive current cancer therapies and to initiate tumor recurrence and metastasis. Recently, different pathways that confer resistance and survival of CSCs, but also compounds and drugs that selectively target some of these pathways in CSCs have been identified. Such compounds and drugs include antibiotics like salinomycin, phytochemicals such as parthenolide, cyclopamine, EGCG, resveratrol, curcumin, sulforaphane and oxymatrine, the small molecule inhibitors vismodegib and repertaxin, monoclonal antibodies and antibody constructs raised against cell surface proteins expressed by CSCs, and, surprisingly, some classical drugs such as metformin, tranilast and thioridazine. These agents exhibit significant anti-CSC activity, alone or in combination with cytostatic drugs or tumor-targeted drugs, as recently shown in vitro and in human xenograft mice. Since current cancer therapies fail to eliminate CSCs, leading to cancer recurrence and progression, selective targeting of CSCs with compounds and drugs introduced herein may represent a novel therapeutic strategy to eradicate cancer. Keywords: Cancer stem cells (CSCs), novel therapeutics, novel drugs, targeted therapy, combination therapy.Download Full Article |
Editor’s Choice : An Audit to Evaluate the Clinical Safety and PSA Response of Firmagon® (Degarelix) in Patients with Advanced Metastatic Prostate Cancer
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Abstract: Objectives: To evaluate the clinical safety and PSA response in patients with metastatic prostate cancer being treated with Firmagon® (Degarelix) and to assess the drug's safety profile. Patients and Methods: This was an audit of 35 patients with PSA levels >50 and advanced metastatic prostate cancer at presentation who received Firmagon® (Degarelix) as per our North East & Cumbria Cancer Drug Approvals Group (NECDAG), UK guidelines. The audit was conducted using results from three hospitals in North East England with an aim to evaluate the safety profile, clinical and PSA response with this new drug. Baseline symptoms at diagnosis, presenting PSA and post treatment parameters on the commencement of with Firmagon® (Degarelix) were recorded. All patients in our cohort were homogenous having had not received any previous treatment including any form of LHRH analogue therapy. PSA levels were measured at 6 weekly intervals initially followed by 3 monthly intervals to evaluate initial and long term response to treatment withFirmagon® (Degarelix). Results: There was no incidence of anaphylaxis or injection site complications on immediate administration ofFirmagon® (Degarelix). No of our patients had renal or liver toxicity in our series. There was no incidence of tumour flare in any patient. A total of 23% of patients who presented primarily with severe bone pain described a complete resolution of Firmagon® (Degarelix) and required no adjuvant treatment such as bisphosphonates or palliative radiotherapy. A significant reduction in PSA levels were noted immediately at 6 weeks and 3 months following treatment with Firmagon® (Degarelix) (p=0.0038). Conclusions: Firmagon® (Degarelix) is a safe drug is well tolerated in patients with advanced metastatic prostate cancer. The reason of how bone pain completely resolves in some patients with extensive bone metastasis on the commencement of Firmagon® (Degarelix) needs to be evaluated. Keywords: Firmagon® (Degarelix), prostate cancer, PSA response, bone pain.Download Full Article |
Editor’s Choice : The Reciprocal Interaction of Small Molecule Protein Kinase Inhibitors and ATP-Binding Cassette Transporters in Targeted Cancer Therapy
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Abstract: Protein kinaseshave become the second most important group of drug targets, after G-protein-coupled receptors. Currently,15 small molecule protein kinase inhibitors (PKIs) have received food and drug administrator (FDA) approval to be used as cancer treatments. However, in the course of clinical use of these small molecule PKIs, drug resistance has become a recurring problem. Their therapeutic potential depends on access to their intracellular targets, which significantly affected by certain membrane ATP-binding cassette(ABC) transporters. ABC transporters were major causesof clinical multiple drug resistance (MDR) and might be resulting in the development of resistance to PKIs in cancer patients. Some PKIs could modulate the activity of ABC transporters and affect the metabolism of themselves and other chemically unrelated drugs. Moreover, it has been recently reported that some PKIs could regulate the expression of ABC transporters in tumor cells, thereby affect their intracellular accumulation and antitumor efficacy. In this review,the reciprocal interaction of clinically important PKIs with the MDR-related ABC transporters, in particular ABCB1 and ABCG2,wassummarized. Keywords: Protein Kinase Inhibitors, ABC Transporters, P-gp/ABCB1, BCRP/ABCG2, Targeted Cancer Therapy.Download Full Article |