The Experts below are selected from a list of 85182 Experts worldwide ranked by ideXlab platform
Kevin Struhl - One of the best experts on this subject based on the ideXlab platform.
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Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Heather A Hirsch, Dimitrios Iliopoulos, Kevin StruhlAbstract:Metformin, the first-line drug for treating diabetes, inhibits cellular transformation and selectively kills cancer stem cells in breast cancer cell lines. In a Src-inducible model of cellular transformation, Metformin inhibits the earliest known step in the process, activation of the inflammatory transcription factor NF-κB. Metformin strongly delays cellular transformation in a manner similar to that occurring upon a weaker inflammatory stimulus. Conversely, inhibition of transformation does not occur if Metformin is added after the initial inflammatory stimulus. The antitransformation effect of Metformin can be bypassed by overexpression of Lin28B or IL1β, downstream targets of NF-κB. Metformin preferentially inhibits nuclear translocation of NF-κB and phosphorylation of STAT3 in cancer stem cells compared with non-stem cancer cells in the same population. The ability of Metformin to block tumor growth and prolong remission in xenografts in combination with doxorubicin is associated with decreased function of the inflammatory feedback loop. Lastly, Metformin-based combinatorial therapy is effective in xenografts involving inflammatory prostate and melanoma cell lines, whereas it is ineffective in noninflammatory cell lines from these lineages. Taken together, our observations suggest that Metformin inhibits a signal transduction pathway that results in an inflammatory response. As Metformin alters energy metabolism in diabetics, we speculate that Metformin may block a metabolic stress response that stimulates the inflammatory pathway associated with a wide variety of cancers.
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Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types
Cancer Research, 2011Co-Authors: Dimitrios Iliopoulos, Heather A Hirsch, Kevin StruhlAbstract:Metformin, the first-line drug for treating diabetes, selectively kills the chemotherapy-resistant, sub-population of cancer stem cells in genetically distinct types of breast cancer cell lines. In mouse xenografts, injection of Metformin and the chemotherapeutic drug doxorubicin near the tumor is more effective than either drug alone in blocking tumor growth and preventing relapse. Here, we show that Metformin is equally effective when given orally together with paclitaxel, carboplatin, and doxorubicin indicating that Metformin works together with a variety of standard chemotherapeutic agents. In addition, Metformin has comparable effects on tumor regression and preventing relapse when Metformin combined with a 4-fold reduced dose of doxorubicin that is not effective as a monotherapy. Lastly, the combination of Metformin and doxorubicin prevents relapse in xenografts generated with prostate and lung cancer cell lines. These observations provide further evidence for the cancer stem cell hypothesis for cancer relapse, as well as an experimental rationale for using Metformin as part of combinatorial therapy in a variety of clinical settings and for reducing the chemotherapy dose in cancer patients.
Chetan S. Karyekar - One of the best experts on this subject based on the ideXlab platform.
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Adding Saxagliptin to Metformin Extended Release (XR) or Uptitration of Metformin XR: Efficacy on Daily Glucose Measures
Diabetes Therapy, 2013Co-Authors: Joel M. Neutel, Cathy Zhao, Chetan S. KaryekarAbstract:Introduction Saxagliptin added to Metformin extended release (XR) and uptitrated Metformin XR were evaluated for their impact on daily glucose measurements and their tolerability in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with Metformin monotherapy. Methods Patients aged 18–78 years on Metformin 850–1,500 mg with glycated hemoglobin (HbA_1c) 7.5–11.5% at screening were eligible for this double-blind, active-controlled study. Patients were stabilized on Metformin XR 1,500 mg before randomization. Patients with HbA_1c 7–11% and fasting plasma glucose (FPG) ≥126 mg/dL after a 4- 8-week lead-in period were randomly assigned to saxagliptin 5 mg + Metformin XR 1,500 mg or Metformin XR 500 mg + Metformin XR 1,500 mg (uptitrated Metformin XR). The primary end point was change from baseline to week 4 in 24-h mean weighted glucose (MWG). Secondary end points were changes from baseline to week 4 in 2-h postprandial glucose (PPG) and FPG. Results At week 4, the adjusted mean ± SE change from baseline in 24-h MWG was −19.0 ± 5.7 mg/dL (95% CI −30.3 to −7.6) for saxagliptin + Metformin XR and −8.2 ± 6.0 mg/dL (95% CI −20.0 to 3.7) for uptitrated Metformin XR. Mean changes from baseline in 2-h PPG and FPG were numerically greater with saxagliptin + Metformin XR versus uptitrated Metformin XR. The incidence of adverse events was lower with saxagliptin + Metformin XR (17.4%) versus uptitrated Metformin XR (31.9%) mainly due to differences in gastrointestinal adverse event incidence (2.2% vs 10.6%, respectively). There were no reports of confirmed hypoglycemia in either group. Conclusion In this 4-week study in patients with T2DM inadequately controlled with Metformin monotherapy, saxagliptin added to Metformin XR demonstrated a trend for improvement in measures of daily glycemic control, with fewer gastrointestinal adverse events, compared with uptitrated Metformin.
Heather A Hirsch - One of the best experts on this subject based on the ideXlab platform.
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Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Heather A Hirsch, Dimitrios Iliopoulos, Kevin StruhlAbstract:Metformin, the first-line drug for treating diabetes, inhibits cellular transformation and selectively kills cancer stem cells in breast cancer cell lines. In a Src-inducible model of cellular transformation, Metformin inhibits the earliest known step in the process, activation of the inflammatory transcription factor NF-κB. Metformin strongly delays cellular transformation in a manner similar to that occurring upon a weaker inflammatory stimulus. Conversely, inhibition of transformation does not occur if Metformin is added after the initial inflammatory stimulus. The antitransformation effect of Metformin can be bypassed by overexpression of Lin28B or IL1β, downstream targets of NF-κB. Metformin preferentially inhibits nuclear translocation of NF-κB and phosphorylation of STAT3 in cancer stem cells compared with non-stem cancer cells in the same population. The ability of Metformin to block tumor growth and prolong remission in xenografts in combination with doxorubicin is associated with decreased function of the inflammatory feedback loop. Lastly, Metformin-based combinatorial therapy is effective in xenografts involving inflammatory prostate and melanoma cell lines, whereas it is ineffective in noninflammatory cell lines from these lineages. Taken together, our observations suggest that Metformin inhibits a signal transduction pathway that results in an inflammatory response. As Metformin alters energy metabolism in diabetics, we speculate that Metformin may block a metabolic stress response that stimulates the inflammatory pathway associated with a wide variety of cancers.
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Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types
Cancer Research, 2011Co-Authors: Dimitrios Iliopoulos, Heather A Hirsch, Kevin StruhlAbstract:Metformin, the first-line drug for treating diabetes, selectively kills the chemotherapy-resistant, sub-population of cancer stem cells in genetically distinct types of breast cancer cell lines. In mouse xenografts, injection of Metformin and the chemotherapeutic drug doxorubicin near the tumor is more effective than either drug alone in blocking tumor growth and preventing relapse. Here, we show that Metformin is equally effective when given orally together with paclitaxel, carboplatin, and doxorubicin indicating that Metformin works together with a variety of standard chemotherapeutic agents. In addition, Metformin has comparable effects on tumor regression and preventing relapse when Metformin combined with a 4-fold reduced dose of doxorubicin that is not effective as a monotherapy. Lastly, the combination of Metformin and doxorubicin prevents relapse in xenografts generated with prostate and lung cancer cell lines. These observations provide further evidence for the cancer stem cell hypothesis for cancer relapse, as well as an experimental rationale for using Metformin as part of combinatorial therapy in a variety of clinical settings and for reducing the chemotherapy dose in cancer patients.
Dimitrios Iliopoulos - One of the best experts on this subject based on the ideXlab platform.
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Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Heather A Hirsch, Dimitrios Iliopoulos, Kevin StruhlAbstract:Metformin, the first-line drug for treating diabetes, inhibits cellular transformation and selectively kills cancer stem cells in breast cancer cell lines. In a Src-inducible model of cellular transformation, Metformin inhibits the earliest known step in the process, activation of the inflammatory transcription factor NF-κB. Metformin strongly delays cellular transformation in a manner similar to that occurring upon a weaker inflammatory stimulus. Conversely, inhibition of transformation does not occur if Metformin is added after the initial inflammatory stimulus. The antitransformation effect of Metformin can be bypassed by overexpression of Lin28B or IL1β, downstream targets of NF-κB. Metformin preferentially inhibits nuclear translocation of NF-κB and phosphorylation of STAT3 in cancer stem cells compared with non-stem cancer cells in the same population. The ability of Metformin to block tumor growth and prolong remission in xenografts in combination with doxorubicin is associated with decreased function of the inflammatory feedback loop. Lastly, Metformin-based combinatorial therapy is effective in xenografts involving inflammatory prostate and melanoma cell lines, whereas it is ineffective in noninflammatory cell lines from these lineages. Taken together, our observations suggest that Metformin inhibits a signal transduction pathway that results in an inflammatory response. As Metformin alters energy metabolism in diabetics, we speculate that Metformin may block a metabolic stress response that stimulates the inflammatory pathway associated with a wide variety of cancers.
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Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types
Cancer Research, 2011Co-Authors: Dimitrios Iliopoulos, Heather A Hirsch, Kevin StruhlAbstract:Metformin, the first-line drug for treating diabetes, selectively kills the chemotherapy-resistant, sub-population of cancer stem cells in genetically distinct types of breast cancer cell lines. In mouse xenografts, injection of Metformin and the chemotherapeutic drug doxorubicin near the tumor is more effective than either drug alone in blocking tumor growth and preventing relapse. Here, we show that Metformin is equally effective when given orally together with paclitaxel, carboplatin, and doxorubicin indicating that Metformin works together with a variety of standard chemotherapeutic agents. In addition, Metformin has comparable effects on tumor regression and preventing relapse when Metformin combined with a 4-fold reduced dose of doxorubicin that is not effective as a monotherapy. Lastly, the combination of Metformin and doxorubicin prevents relapse in xenografts generated with prostate and lung cancer cell lines. These observations provide further evidence for the cancer stem cell hypothesis for cancer relapse, as well as an experimental rationale for using Metformin as part of combinatorial therapy in a variety of clinical settings and for reducing the chemotherapy dose in cancer patients.
David Henry - One of the best experts on this subject based on the ideXlab platform.
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glyburide Metformin combination product is safe and efficacious in patients with type 2 diabetes failing sulphonylurea therapy
Diabetes Obesity and Metabolism, 2002Co-Authors: Laurent Blonde, Julio Rosenstock, Arshag D. Mooradian, B A Piper, David HenryAbstract:Aim: To compare the efficacy, safety and tolerability of a fixed combination glyburide/Metformin preparation with those of glyburide or Metformin alone in patients with type 2 diabetes inadequately controlled by sulphonylurea, diet and exercise. Methods: In this 16-week, randomized, double-blind, parallel group study, 639 patients with inadequate glycaemic control on at least half-maximal dose of sulphonylurea were randomly assigned to: glyburide 10 mg b.i.d. (n = 164); Metformin 500 mg (n = 153); glyburide/Metformin 2.5 mg/500 mg (n = 160); or glyburide/Metformin 5 mg/500 mg (n = 162). Titration was allowed to maximum doses of 2000 mg for Metformin or 10 mg/2000 mg and 20 mg/2000 mg for glyburide/Metformin 2.5 mg/500 mg and 5 mg/500 mg respectively. The primary outcome measure was HbA1c level after 16 weeks; secondary end-points included fasting and 2-h post-prandial plasma glucose. Adverse events (AEs) were recorded and summarized by treatment group. Results: Both strengths of glyburide/Metformin equally reduced mean HbA1c by 1.7% more than did glyburide alone (p < 0.001), and by 1.9% more than did Metformin alone (p < 0.001). Final mean fasting plasma glucose concentrations were also lower in both glyburide/Metformin groups than in the glyburide (−2.8 mmol/l, −51.3 mg/dl; p < 0.001) and Metformin groups (−3.6 mmol/l, −64.2 mg/dl; p < 0.001). Safety and tolerability were similar across all treatment groups, except for a higher incidence of gastrointestinal AEs in the Metformin monotherapy group, and more patients reporting mild or moderate symptoms of hypoglycaemia while taking glyburide/Metformin. Conclusions: Both glyburide/Metformin tablet strengths produced, with equal efficacy, significantly better glycaemic control than monotherapy with either agent. These data also confirm that glycaemic efficacy does not require maximal sulphonylurea doses in combination with Metformin.
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simultaneous glyburide Metformin therapy is superior to component monotherapy as an initial pharmacological treatment for type 2 diabetes
Diabetes Obesity and Metabolism, 2002Co-Authors: Alan J. Garber, B A Piper, Jennifer Lynn Larsen, S H Schneider, David HenryAbstract:Objective: To evaluate whether simultaneous initial treatment of both insulin resistance and impaired β-cell insulin secretion with glyburide/Metformin tablets is superior to monotherapy with each component agent. Research Design and Methods: In this randomized, parallel-group, placebo-controlled, multicentre study, 806 patients with type 2 diabetes (mean duration, 3 years) who had failed diet and exercise were randomly assigned to 4 weeks of therapy with placebo, glyburide 2.5 mg, Metformin 500 mg, glyburide/Metformin 1.25/250 mg, or glyburide/Metformin 2.5/500 mg once daily. Doses were then titrated over 8 weeks based on glycaemic response. The primary outcome measure was change from baseline in mean HbA1c after 20 weeks. Changes in fasting plasma glucose, lipids and body weight were also assessed along with 2-h postprandial glucose and insulin values after a standardized meal. Results: At week 20, patients taking glyburide/Metformin 1.25/250 mg or 2.5/500 mg tablets had greater reductions in HbA1c levels (−1.48% and −1.53% respectively) compared with placebo (−0.21%; both p < 0.001), glyburide (−1.24%; p = 0.016 and p = 0.004 respectively) or Metformin (−1.03%; both p < 0.001). Fasting plasma glucose concentrations were reduced more in both glyburide/Metformin groups compared with placebo and Metformin (p < 0.001); patients in both combination therapy groups also had significantly lower postprandial glucose concentrations compared with placebo, glyburide and Metformin. Conclusions: Initial combination treatment with glyburide/Metformin tablets produces greater improvements in glycaemic control than either glyburide or Metformin monotherapy. The superiority of initial therapy with glyburide/Metformin tablets may arise from simultaneous treatment of both pathophysiological defects of type 2 diabetes.
