The Experts below are selected from a list of 1056 Experts worldwide ranked by ideXlab platform
Benoit Viollet - One of the best experts on this subject based on the ideXlab platform.
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Phenformin but not metformin delays development of t cell acute lymphoblastic leukemia lymphoma via cell autonomous ampk activation
Cell Reports, 2019Co-Authors: Diana Varaciruelos, Madhumita Dandapani, Fiona M. Russell, Katarzyna M. Grzes, Abdelmadjid Atrih, Marc Foretz, Benoit ViolletAbstract:Summary AMPK acts downstream of the tumor suppressor LKB1, yet its role in cancer has been controversial. AMPK is activated by biguanides, such as metformin and Phenformin, and metformin use in diabetics has been associated with reduced cancer risk. However, whether this is mediated by cell-autonomous AMPK activation within tumor progenitor cells has been unclear. We report that T-cell-specific loss of AMPK-α1 caused accelerated growth of T cell acute lymphoblastic leukemia/lymphoma (T-ALL) induced by PTEN loss in thymic T cell progenitors. Oral administration of Phenformin, but not metformin, delayed onset and growth of lymphomas, but only when T cells expressed AMPK-α1. This differential effect of biguanides correlated with detection of Phenformin, but not metformin, in thymus. Phenformin also enhanced apoptosis in T-ALL cells both in vivo and in vitro. Thus, AMPK-α1 can be a cell-autonomous tumor suppressor in the context of T-ALL, and Phenformin may have potential for the prevention of some cancers.
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Phenformin, But Not Metformin, Delays Development of T Cell Acute Lymphoblastic Leukemia/Lymphoma via Cell-Autonomous AMPK Activation
Cell Reports, 2019Co-Authors: Diana Vara-ciruelos, Madhumita Dandapani, Katarzyna M. Grzes, Abdelmadjid Atrih, Marc Foretz, Benoit Viollet, Fiona Russell, Douglas Lamont, Doreen Cantrell, D Grahame HardieAbstract:AMPK acts downstream of the tumor suppressor LKB1, yet its role in cancer has been controversial. AMPK is activated by biguanides, such as metformin and Phenformin, and metformin use in diabetics has been associated with reduced cancer risk. However, whether this is mediated by cell-autonomous AMPK activation within tumor progenitor cells has been unclear. We report that T-cell-specific loss of AMPK-α1 caused accelerated growth of T cell acute lymphoblastic leukemia/lymphoma (T-ALL) induced by PTEN loss in thymic T cell progenitors. Oral administration of Phenformin, but not metformin, delayed onset and growth of lymphomas, but only when T cells expressed AMPK-α1. This differential effect of biguanides correlated with detection of Phenformin, but not metformin, in thymus. Phenformin also enhanced apoptosis in T-ALL cells both in vivo and in vitro. Thus, AMPK-α1 can be a cell-autonomous tumor suppressor in the context of T-ALL, and Phenformin may have potential for the prevention of some cancers.
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Phenformin, But Not Metformin, Delays Development of T Cell Acute Lymphoblastic Leukemia/Lymphoma via Cell-Autonomous AMPK Activation
Elsevier, 2019Co-Authors: Diana Vara-ciruelos, Madhumita Dandapani, Fiona M. Russell, Katarzyna M. Grzes, Abdelmadjid Atrih, Marc Foretz, Benoit Viollet, Douglas J. Lamont, Doreen A. Cantrell, Grahame D. HardieAbstract:Summary: AMPK acts downstream of the tumor suppressor LKB1, yet its role in cancer has been controversial. AMPK is activated by biguanides, such as metformin and Phenformin, and metformin use in diabetics has been associated with reduced cancer risk. However, whether this is mediated by cell-autonomous AMPK activation within tumor progenitor cells has been unclear. We report that T-cell-specific loss of AMPK-α1 caused accelerated growth of T cell acute lymphoblastic leukemia/lymphoma (T-ALL) induced by PTEN loss in thymic T cell progenitors. Oral administration of Phenformin, but not metformin, delayed onset and growth of lymphomas, but only when T cells expressed AMPK-α1. This differential effect of biguanides correlated with detection of Phenformin, but not metformin, in thymus. Phenformin also enhanced apoptosis in T-ALL cells both in vivo and in vitro. Thus, AMPK-α1 can be a cell-autonomous tumor suppressor in the context of T-ALL, and Phenformin may have potential for the prevention of some cancers. : The roles of AMPK in cancer and of biguanides in its prevention or treatment are controversial. Vara-Ciruelos et al. now report that genetic loss of AMPK in T cells accelerates T cell acute lymphoblastic leukemia/lymphoma, whereas the biguanide Phenformin, but not metformin, protects against its development in a cell-autonomous, AMPK-dependent manner. Keywords: AMP-activated protein kinase, AMPK, biguanides, metformin, Phenformin, T-ALL, T cell acute lymphoblastic leukemia/lymphom
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AMPK Signaling Involvement for the Repression of the IL-1β-Induced Group IIA Secretory Phospholipase A2 Expression in VSMCs
PLoS ONE, 2015Co-Authors: Khadija El Hadri, Marc Foretz, Benoit Viollet, Chantal Denoyelle, Lucas Ravaux, Bertrand Friguet, Mustapha Rouis, Michel RaymondjeanAbstract:Secretory Phospholipase A2 of type IIA (sPLA2 IIA) plays a crucial role in the production of lipid mediators by amplifying the neointimal inflammatory context of the vascular smooth muscle cells (VSMCs), especially during atherogenesis. Phenformin, a biguanide family member, by its anti-inflammatory properties presents potential for promoting beneficial effects upon vascular cells, however its impact upon the IL-1β-induced sPLA2 gene expression has not been deeply investigated so far. The present study was designed to determine the relationship between Phenformin coupling AMP-activated protein kinase (AMPK) function and the molecular mechanism by which the sPLA2 IIA expression was modulated in VSMCs. Here we find that 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleotide (AICAR) treatment strongly repressed IL-1β-induced sPLA2 expression at least at the transcriptional level. Our study reveals that Phenformin elicited a dose-dependent inhibition of the sPLA2 IIA expression and transient overexpression experiments of constitutively active AMPK demonstrate clearly that AMPK signaling is involved in the transcriptional inhibition of sPLA2-IIA gene expression. Furthermore, although the expression of the transcriptional repressor B-cell lymphoma-6 protein (BCL-6) was markedly enhanced by Phenformin and AICAR, the repression of sPLA2 gene occurs through a mechanism independent of BCL-6 DNA binding site. In addition we show that activation of AMPK limits IL-1β-induced NF-κB pathway activation. Our results indicate that BCL-6, once activated by AMPK, functions as a competitor of the IL-1β induced NF-κB transcription complex. Our findings provide insights on a new anti-inflammatory pathway linking Phenformin, AMPK and molecular control of sPLA2 IIA gene expression in VSMCs.
Victoria L Baejump - One of the best experts on this subject based on the ideXlab platform.
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abstract 1313 anti tumorigenic effects of Phenformin in human endometrial cancer cells
Cancer Research, 2014Co-Authors: Amanda L Jackson, Joshua Kilgore, Haifeng Qiu, Chunxiao Zhou, Paola A Gehrig, Victoria L BaejumpAbstract:Introduction: The anti-diabetic drugs, metformin and Phenformin, are thought to have anti-tumorigenic benefits. Preclinical studies suggest that Phenformin may be more potent for inhibiting tumor growth than metformin. Our objective was to assess the anti-tumorigenic effects of Phenformin in endometrial cancer (EC) cell lines and primary cultures. Methods: The EC cell lines, ECC-1 and Ishikawa, were treated with Phenformin under low glucose (2 mM), normal glucose (5.5 mM) and high glucose (25 mM) conditions. EC tumors were collected from consenting patients, at the time of surgical staging for primary culture. Cell proliferation was assessed by MTT assay. Apoptosis was analyzed by Annexin V-FITC assay. Cellometer evaluated cell cycle progression. Invasion was demonstrated by transwell invasion assay. Adhesion was assessed by ELISA. Western blotting was performed to determine expression of the downstream targets of Phenformin. Results: Phenformin inhibited proliferation in a dose-dependent manner in both EC cell lines, within 48-72 hrs of exposure (IC50=1 mM, p=0.0004-0.009). Inhibition of proliferation was seen for all glucose concentrations, but greater potency was observed under low glucose conditions. Treatment with Phenformin resulted in G1 arrest, induction of apoptosis (p=0.022-0.017) and inhibition of adhesion (p=0.0053-0.0144) and invasion (p=0.0063-0.05). Phenformin increased p21 and p27 and decreased cyclin D, cyclin E2, CDK4 and CDK 6, corresponding with G1 arrest. Phenformin significantly inhibited proliferation in 62% (8/13) of the EC primary cultures, within 48-72 hrs of exposure (IC50 0.1-5mM, p=0.00001-0.016). 3 additional EC samples (23%) were significantly inhibited by Phenformin but did not reach an IC50 (p=0.0003-0.018), and 2/13 (15%) had no response to Phenformin. Western blot analysis demonstrated that Phenformin increased phosphorylation of AMPK and decreased phosphorylation of S6 coincident with inhibition of proliferation in the EC cell lines and primary cultures. Conclusion: Phenformin potently inhibited cell growth via G1 arrest and induced apoptosis in EC cell lines and the majority of primary cultures. Inhibition of adhesion/invasion was also seen with Phenformin. Continued work is needed to explore whether Phenformin has superior benefits over metformin. Citation Format: Amanda L. Jackson, Joshua E. Kilgore, Haifeng Qiu, Chunxiao Zhou, Paola A. Gehrig, Victoria L. Bae-Jump. Anti-tumorigenic effects of Phenformin in human endometrial cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1313. doi:10.1158/1538-7445.AM2014-1313
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abstract 3113 Phenformin has anti tumorigenic effects in human ovarian cancer cells and in a genetically engineered mouse model of serous ovarian cancer
Cancer Research, 2014Co-Authors: Amanda L Jackson, Joshua Kilgore, Chunxiao Zhou, Xiaoyun Han, Liza Makowski, Victoria L BaejumpAbstract:Objectives: Anti-diabetic biguanide drugs have been shown to have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Phenformin is a biguanide that is associated with a higher risk of lactic acidosis than is seen in metformin. In vitro and in vivo studies suggest that Phenformin may be more potent for inhibiting tumor growth than metformin. We sought to examine the efficacy of Phenformin in primary cultures of human ovarian cancers (OCs) as well as in a genetically engineered mouse model of serous OC. Methods: Serous OC tumors were collected from consenting patients, at the time of their surgical debulking for primary culture. Cell proliferation was assessed by MTT assay. Apoptosis was evaluated by Annexin V-FITC assay using Cellometer. Effects of Phenformin on phosphorylated-AMPK and -S6 expression was documented by Western immunoblotting. For the in vivo studies, we utilized the KpB++ serous OC mouse model. This is a more aggressive derivative of the K18-gT121+/-; p53fl/fl;Brca1fl/fl (KpB) genetically engineered OC mouse model. The KpB++ mice were treated with placebo or Phenformin (2 mg/kg body weight in drinking water) following tumor onset for one month. Immunohistochemical analysis was performed on the ovarian tumors after treatment with placebo or Phenformin, in regards to Ki-67 expression, cleaved caspase 3 (a marker of apoptosis), phosphorylated AMPK and phosphorylated S6. Individual slides were digitized using the Aperio ScanScope (Aperio Technologies, Vista, CA), and digital images were analyzed using Aperio ImageScope software. Results: Phenformin significantly inhibited cell proliferation in a dose-dependent manner in 100% (7/7) of the primary cultures of ovarian tumors, within 48 to 72 hours of exposure (p=0.00001-0.015, IC50 range of 0.1-5 mM). Treatment with Phenformin resulted in the induction of apoptosis in 71.4% (5/7) of the ovarian tumors. Western immunoblot analysis demonstrated that Phenformin increased phosphorylation of AMPK and decreased phosphorylation of S6. Phenformin significantly inhibited tumor growth in the KpB++ mice (n=8-13 animals per group) by 68% as compared to placebo treated controls, after one month of treatment (p=0.016). As compared to the placebo treated control animals, Phenformin was found to statistically decrease Ki67 staining, inhibit phosphorylated S6 expression and increase both cleaved caspase 3 and phosphorylated AMPK expression (p= 0.01-0.04). Conclusions: In primary culture of human serous OC tumors, Phenformin potently inhibited cell growth and increased apoptotic cell death through AMPK activation and mTOR pathway inhibition. In vivo studies using the KpB++ mouse model found that Phenformin was highly efficacious in inhibiting tumor growth. Although the risk/benefit ratio clearly favors metformin over Phenformin for the treatment of diabetes, this may not hold true for the treatment of cancer. Citation Format: Amanda L. Jackson, Xiaoyun Han, Joshua E. Kilgore, Chunxiao Zhou, Liza Makowski, Victoria Bae-Jump. Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in a genetically engineered mouse model of serous ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3113. doi:10.1158/1538-7445.AM2014-3113
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abstract 2442 antitumorigenic effects of Phenformin in human ovarian cancer cell lines
Cancer Research, 2013Co-Authors: Amanda L Jackson, Joshua Kilgore, Haifeng Qiu, Chunxiao Zhou, Paola A Gehrig, Victoria L BaejumpAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: Anti-diabetic biguanide drugs, such as metformin, have been shown to have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Phenformin is another biguanide with anti-diabetic activity that was withdrawn from the market due to a risk of lactic acidosis that was higher than that seen with metformin. In vitro and in vivo studies suggest that Phenformin may be more potent for inhibiting tumor growth than metformin. Thus, our objective was to assess the effect of Phenformin on proliferation and apoptosis in ovarian cancer cell lines. Methods: Three ovarian cell lines, SKOV3, IGROV1, and HEY, were used. Cell proliferation was assessed by MTT assay after exposure to Phenformin and after exposure to Phenformin under varying glucose levels. Apoptosis was analyzed by Annexin V-FITC assay. Cell cycle progression was evaluated by Cellometer. Western immunoblotting was performed to determine expression of the downstream targets of Phenformin, including AMPK, ribosomal protein S6, cyclin D and E2, cyclin dependent kinase (CDK) 4 and 6, p21 and p27. Inhibition of adhesion by Phenformin was assessed by in vitro adhesion assay. Results: Phenformin potently inhibited proliferation in a dose-dependent manner in all three ovarian cancer cell lines (IC50 = 2.5mM for SKOV3 and HEY, 1mM for IGROV1 at 48 hours) (p = 0.0035 – 0.00001). Inhibition of proliferation was found at normal, low and high glucose concentrations, but greater potency was observed under low glucose concentrations. Treatment with Phenformin resulted in G1 cell cycle arrest and induction of apoptosis. Cellular adhesion was decreased by 14-32% in the ovarian cancer cell lines at a Phenformin dose of 2.5mM (p = 0.009 – 0.0001). Western immunoblot analysis demonstrated that Phenformin induced phosphorylation of AMPK, its immediate downstream mediator, within 18 hours of exposure. In parallel, treatment with Phenformin decreased phosphorylation of the S6 protein, a key target of the mTOR pathway. Phenformin was also found to increase the cell cycle inhibitors, p21 and p27, and decrease cyclin D, cyclin E2, CDK4 and CDK 6, corresponding with G1 arrest in these cell lines. Conclusion: Phenformin potently inhibited ovarian cancer cell growth via G1 arrest and increased apoptosis. Although the risk/benefit ratio clearly favors metformin over Phenformin for the treatment of diabetes, this may not hold true for the treatment of cancer if Phenformin were found to have superior anti-tumorigenic activity. Continued work is needed to explore the benefits of both metformin and Phenformin for the treatment of ovarian cancer and the optimal therapeutic index. Citation Format: Amanda L. Jackson, Joshua E. Kilgore, Haifeng Qiu, Chunxiao Zhou, Paola A. Gehrig, Victoria L. Bae-Jump. Antitumorigenic effects of Phenformin in human ovarian cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2442. doi:10.1158/1538-7445.AM2013-2442
Marc Foretz - One of the best experts on this subject based on the ideXlab platform.
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Phenformin but not metformin delays development of t cell acute lymphoblastic leukemia lymphoma via cell autonomous ampk activation
Cell Reports, 2019Co-Authors: Diana Varaciruelos, Madhumita Dandapani, Fiona M. Russell, Katarzyna M. Grzes, Abdelmadjid Atrih, Marc Foretz, Benoit ViolletAbstract:Summary AMPK acts downstream of the tumor suppressor LKB1, yet its role in cancer has been controversial. AMPK is activated by biguanides, such as metformin and Phenformin, and metformin use in diabetics has been associated with reduced cancer risk. However, whether this is mediated by cell-autonomous AMPK activation within tumor progenitor cells has been unclear. We report that T-cell-specific loss of AMPK-α1 caused accelerated growth of T cell acute lymphoblastic leukemia/lymphoma (T-ALL) induced by PTEN loss in thymic T cell progenitors. Oral administration of Phenformin, but not metformin, delayed onset and growth of lymphomas, but only when T cells expressed AMPK-α1. This differential effect of biguanides correlated with detection of Phenformin, but not metformin, in thymus. Phenformin also enhanced apoptosis in T-ALL cells both in vivo and in vitro. Thus, AMPK-α1 can be a cell-autonomous tumor suppressor in the context of T-ALL, and Phenformin may have potential for the prevention of some cancers.
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Phenformin, But Not Metformin, Delays Development of T Cell Acute Lymphoblastic Leukemia/Lymphoma via Cell-Autonomous AMPK Activation
Cell Reports, 2019Co-Authors: Diana Vara-ciruelos, Madhumita Dandapani, Katarzyna M. Grzes, Abdelmadjid Atrih, Marc Foretz, Benoit Viollet, Fiona Russell, Douglas Lamont, Doreen Cantrell, D Grahame HardieAbstract:AMPK acts downstream of the tumor suppressor LKB1, yet its role in cancer has been controversial. AMPK is activated by biguanides, such as metformin and Phenformin, and metformin use in diabetics has been associated with reduced cancer risk. However, whether this is mediated by cell-autonomous AMPK activation within tumor progenitor cells has been unclear. We report that T-cell-specific loss of AMPK-α1 caused accelerated growth of T cell acute lymphoblastic leukemia/lymphoma (T-ALL) induced by PTEN loss in thymic T cell progenitors. Oral administration of Phenformin, but not metformin, delayed onset and growth of lymphomas, but only when T cells expressed AMPK-α1. This differential effect of biguanides correlated with detection of Phenformin, but not metformin, in thymus. Phenformin also enhanced apoptosis in T-ALL cells both in vivo and in vitro. Thus, AMPK-α1 can be a cell-autonomous tumor suppressor in the context of T-ALL, and Phenformin may have potential for the prevention of some cancers.
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Phenformin, But Not Metformin, Delays Development of T Cell Acute Lymphoblastic Leukemia/Lymphoma via Cell-Autonomous AMPK Activation
Elsevier, 2019Co-Authors: Diana Vara-ciruelos, Madhumita Dandapani, Fiona M. Russell, Katarzyna M. Grzes, Abdelmadjid Atrih, Marc Foretz, Benoit Viollet, Douglas J. Lamont, Doreen A. Cantrell, Grahame D. HardieAbstract:Summary: AMPK acts downstream of the tumor suppressor LKB1, yet its role in cancer has been controversial. AMPK is activated by biguanides, such as metformin and Phenformin, and metformin use in diabetics has been associated with reduced cancer risk. However, whether this is mediated by cell-autonomous AMPK activation within tumor progenitor cells has been unclear. We report that T-cell-specific loss of AMPK-α1 caused accelerated growth of T cell acute lymphoblastic leukemia/lymphoma (T-ALL) induced by PTEN loss in thymic T cell progenitors. Oral administration of Phenformin, but not metformin, delayed onset and growth of lymphomas, but only when T cells expressed AMPK-α1. This differential effect of biguanides correlated with detection of Phenformin, but not metformin, in thymus. Phenformin also enhanced apoptosis in T-ALL cells both in vivo and in vitro. Thus, AMPK-α1 can be a cell-autonomous tumor suppressor in the context of T-ALL, and Phenformin may have potential for the prevention of some cancers. : The roles of AMPK in cancer and of biguanides in its prevention or treatment are controversial. Vara-Ciruelos et al. now report that genetic loss of AMPK in T cells accelerates T cell acute lymphoblastic leukemia/lymphoma, whereas the biguanide Phenformin, but not metformin, protects against its development in a cell-autonomous, AMPK-dependent manner. Keywords: AMP-activated protein kinase, AMPK, biguanides, metformin, Phenformin, T-ALL, T cell acute lymphoblastic leukemia/lymphom
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AMPK Signaling Involvement for the Repression of the IL-1β-Induced Group IIA Secretory Phospholipase A2 Expression in VSMCs
PLoS ONE, 2015Co-Authors: Khadija El Hadri, Marc Foretz, Benoit Viollet, Chantal Denoyelle, Lucas Ravaux, Bertrand Friguet, Mustapha Rouis, Michel RaymondjeanAbstract:Secretory Phospholipase A2 of type IIA (sPLA2 IIA) plays a crucial role in the production of lipid mediators by amplifying the neointimal inflammatory context of the vascular smooth muscle cells (VSMCs), especially during atherogenesis. Phenformin, a biguanide family member, by its anti-inflammatory properties presents potential for promoting beneficial effects upon vascular cells, however its impact upon the IL-1β-induced sPLA2 gene expression has not been deeply investigated so far. The present study was designed to determine the relationship between Phenformin coupling AMP-activated protein kinase (AMPK) function and the molecular mechanism by which the sPLA2 IIA expression was modulated in VSMCs. Here we find that 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleotide (AICAR) treatment strongly repressed IL-1β-induced sPLA2 expression at least at the transcriptional level. Our study reveals that Phenformin elicited a dose-dependent inhibition of the sPLA2 IIA expression and transient overexpression experiments of constitutively active AMPK demonstrate clearly that AMPK signaling is involved in the transcriptional inhibition of sPLA2-IIA gene expression. Furthermore, although the expression of the transcriptional repressor B-cell lymphoma-6 protein (BCL-6) was markedly enhanced by Phenformin and AICAR, the repression of sPLA2 gene occurs through a mechanism independent of BCL-6 DNA binding site. In addition we show that activation of AMPK limits IL-1β-induced NF-κB pathway activation. Our results indicate that BCL-6, once activated by AMPK, functions as a competitor of the IL-1β induced NF-κB transcription complex. Our findings provide insights on a new anti-inflammatory pathway linking Phenformin, AMPK and molecular control of sPLA2 IIA gene expression in VSMCs.
Chunxiao Zhou - One of the best experts on this subject based on the ideXlab platform.
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Phenformin has anti tumorigenic effects in human ovarian cancer cells and in an orthotopic mouse model of serous ovarian cancer
Oncotarget, 2017Co-Authors: Amanda Jackson, Joshua Kilgore, Yajie Yin, Ziwei Fang, Wenchuan Sun, Hui Guo, Hannah M Jones, Timothy P Gilliam, Chunxiao ZhouAbstract:Obesity and diabetes have been associated with increased risk and worse outcomes in ovarian cancer (OC). The biguanide metformin is used in the treatment of type 2 diabetes and is also believed to have anti-tumorigenic benefits. Metformin is highly hydrophilic and requires organic cation transporters (OCTs) for entry into human cells. Phenformin, another biguanide, was taken off the market due to an increased risk of lactic acidosis over metformin. However, Phenformin is not reliant on transporters for cell entry; and thus, may have increased potency as both an anti-diabetic and anti-tumorigenic agent than metformin. Thus, our goal was to evaluate the effect of Phenformin on established OC cell lines, primary cultures of human OC cells and in an orthotopic mouse model of high grade serous OC. In three OC cell lines, Phenformin significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, caused cellular stress, inhibited adhesion and invasion, and activation of AMPK and inhibition of the mTOR pathway. Phenformin also exerted anti-proliferative effects in seven primary cell cultures of human OC. Lastly, Phenformin inhibited tumor growth in an orthotopic mouse model of serous OC, coincident with decreased Ki-67 staining and phosphorylated-S6 expression and increased expression of caspase 3 and phosphorylated-AMPK. Our findings demonstrate that Phenformin has anti-tumorigenic effects in OC as previously demonstrated by metformin but it is yet to be determined if it is superior to metformin for the potential treatment of this disease.
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abstract 1313 anti tumorigenic effects of Phenformin in human endometrial cancer cells
Cancer Research, 2014Co-Authors: Amanda L Jackson, Joshua Kilgore, Haifeng Qiu, Chunxiao Zhou, Paola A Gehrig, Victoria L BaejumpAbstract:Introduction: The anti-diabetic drugs, metformin and Phenformin, are thought to have anti-tumorigenic benefits. Preclinical studies suggest that Phenformin may be more potent for inhibiting tumor growth than metformin. Our objective was to assess the anti-tumorigenic effects of Phenformin in endometrial cancer (EC) cell lines and primary cultures. Methods: The EC cell lines, ECC-1 and Ishikawa, were treated with Phenformin under low glucose (2 mM), normal glucose (5.5 mM) and high glucose (25 mM) conditions. EC tumors were collected from consenting patients, at the time of surgical staging for primary culture. Cell proliferation was assessed by MTT assay. Apoptosis was analyzed by Annexin V-FITC assay. Cellometer evaluated cell cycle progression. Invasion was demonstrated by transwell invasion assay. Adhesion was assessed by ELISA. Western blotting was performed to determine expression of the downstream targets of Phenformin. Results: Phenformin inhibited proliferation in a dose-dependent manner in both EC cell lines, within 48-72 hrs of exposure (IC50=1 mM, p=0.0004-0.009). Inhibition of proliferation was seen for all glucose concentrations, but greater potency was observed under low glucose conditions. Treatment with Phenformin resulted in G1 arrest, induction of apoptosis (p=0.022-0.017) and inhibition of adhesion (p=0.0053-0.0144) and invasion (p=0.0063-0.05). Phenformin increased p21 and p27 and decreased cyclin D, cyclin E2, CDK4 and CDK 6, corresponding with G1 arrest. Phenformin significantly inhibited proliferation in 62% (8/13) of the EC primary cultures, within 48-72 hrs of exposure (IC50 0.1-5mM, p=0.00001-0.016). 3 additional EC samples (23%) were significantly inhibited by Phenformin but did not reach an IC50 (p=0.0003-0.018), and 2/13 (15%) had no response to Phenformin. Western blot analysis demonstrated that Phenformin increased phosphorylation of AMPK and decreased phosphorylation of S6 coincident with inhibition of proliferation in the EC cell lines and primary cultures. Conclusion: Phenformin potently inhibited cell growth via G1 arrest and induced apoptosis in EC cell lines and the majority of primary cultures. Inhibition of adhesion/invasion was also seen with Phenformin. Continued work is needed to explore whether Phenformin has superior benefits over metformin. Citation Format: Amanda L. Jackson, Joshua E. Kilgore, Haifeng Qiu, Chunxiao Zhou, Paola A. Gehrig, Victoria L. Bae-Jump. Anti-tumorigenic effects of Phenformin in human endometrial cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1313. doi:10.1158/1538-7445.AM2014-1313
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abstract 3113 Phenformin has anti tumorigenic effects in human ovarian cancer cells and in a genetically engineered mouse model of serous ovarian cancer
Cancer Research, 2014Co-Authors: Amanda L Jackson, Joshua Kilgore, Chunxiao Zhou, Xiaoyun Han, Liza Makowski, Victoria L BaejumpAbstract:Objectives: Anti-diabetic biguanide drugs have been shown to have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Phenformin is a biguanide that is associated with a higher risk of lactic acidosis than is seen in metformin. In vitro and in vivo studies suggest that Phenformin may be more potent for inhibiting tumor growth than metformin. We sought to examine the efficacy of Phenformin in primary cultures of human ovarian cancers (OCs) as well as in a genetically engineered mouse model of serous OC. Methods: Serous OC tumors were collected from consenting patients, at the time of their surgical debulking for primary culture. Cell proliferation was assessed by MTT assay. Apoptosis was evaluated by Annexin V-FITC assay using Cellometer. Effects of Phenformin on phosphorylated-AMPK and -S6 expression was documented by Western immunoblotting. For the in vivo studies, we utilized the KpB++ serous OC mouse model. This is a more aggressive derivative of the K18-gT121+/-; p53fl/fl;Brca1fl/fl (KpB) genetically engineered OC mouse model. The KpB++ mice were treated with placebo or Phenformin (2 mg/kg body weight in drinking water) following tumor onset for one month. Immunohistochemical analysis was performed on the ovarian tumors after treatment with placebo or Phenformin, in regards to Ki-67 expression, cleaved caspase 3 (a marker of apoptosis), phosphorylated AMPK and phosphorylated S6. Individual slides were digitized using the Aperio ScanScope (Aperio Technologies, Vista, CA), and digital images were analyzed using Aperio ImageScope software. Results: Phenformin significantly inhibited cell proliferation in a dose-dependent manner in 100% (7/7) of the primary cultures of ovarian tumors, within 48 to 72 hours of exposure (p=0.00001-0.015, IC50 range of 0.1-5 mM). Treatment with Phenformin resulted in the induction of apoptosis in 71.4% (5/7) of the ovarian tumors. Western immunoblot analysis demonstrated that Phenformin increased phosphorylation of AMPK and decreased phosphorylation of S6. Phenformin significantly inhibited tumor growth in the KpB++ mice (n=8-13 animals per group) by 68% as compared to placebo treated controls, after one month of treatment (p=0.016). As compared to the placebo treated control animals, Phenformin was found to statistically decrease Ki67 staining, inhibit phosphorylated S6 expression and increase both cleaved caspase 3 and phosphorylated AMPK expression (p= 0.01-0.04). Conclusions: In primary culture of human serous OC tumors, Phenformin potently inhibited cell growth and increased apoptotic cell death through AMPK activation and mTOR pathway inhibition. In vivo studies using the KpB++ mouse model found that Phenformin was highly efficacious in inhibiting tumor growth. Although the risk/benefit ratio clearly favors metformin over Phenformin for the treatment of diabetes, this may not hold true for the treatment of cancer. Citation Format: Amanda L. Jackson, Xiaoyun Han, Joshua E. Kilgore, Chunxiao Zhou, Liza Makowski, Victoria Bae-Jump. Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in a genetically engineered mouse model of serous ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3113. doi:10.1158/1538-7445.AM2014-3113
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abstract 2442 antitumorigenic effects of Phenformin in human ovarian cancer cell lines
Cancer Research, 2013Co-Authors: Amanda L Jackson, Joshua Kilgore, Haifeng Qiu, Chunxiao Zhou, Paola A Gehrig, Victoria L BaejumpAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: Anti-diabetic biguanide drugs, such as metformin, have been shown to have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Phenformin is another biguanide with anti-diabetic activity that was withdrawn from the market due to a risk of lactic acidosis that was higher than that seen with metformin. In vitro and in vivo studies suggest that Phenformin may be more potent for inhibiting tumor growth than metformin. Thus, our objective was to assess the effect of Phenformin on proliferation and apoptosis in ovarian cancer cell lines. Methods: Three ovarian cell lines, SKOV3, IGROV1, and HEY, were used. Cell proliferation was assessed by MTT assay after exposure to Phenformin and after exposure to Phenformin under varying glucose levels. Apoptosis was analyzed by Annexin V-FITC assay. Cell cycle progression was evaluated by Cellometer. Western immunoblotting was performed to determine expression of the downstream targets of Phenformin, including AMPK, ribosomal protein S6, cyclin D and E2, cyclin dependent kinase (CDK) 4 and 6, p21 and p27. Inhibition of adhesion by Phenformin was assessed by in vitro adhesion assay. Results: Phenformin potently inhibited proliferation in a dose-dependent manner in all three ovarian cancer cell lines (IC50 = 2.5mM for SKOV3 and HEY, 1mM for IGROV1 at 48 hours) (p = 0.0035 – 0.00001). Inhibition of proliferation was found at normal, low and high glucose concentrations, but greater potency was observed under low glucose concentrations. Treatment with Phenformin resulted in G1 cell cycle arrest and induction of apoptosis. Cellular adhesion was decreased by 14-32% in the ovarian cancer cell lines at a Phenformin dose of 2.5mM (p = 0.009 – 0.0001). Western immunoblot analysis demonstrated that Phenformin induced phosphorylation of AMPK, its immediate downstream mediator, within 18 hours of exposure. In parallel, treatment with Phenformin decreased phosphorylation of the S6 protein, a key target of the mTOR pathway. Phenformin was also found to increase the cell cycle inhibitors, p21 and p27, and decrease cyclin D, cyclin E2, CDK4 and CDK 6, corresponding with G1 arrest in these cell lines. Conclusion: Phenformin potently inhibited ovarian cancer cell growth via G1 arrest and increased apoptosis. Although the risk/benefit ratio clearly favors metformin over Phenformin for the treatment of diabetes, this may not hold true for the treatment of cancer if Phenformin were found to have superior anti-tumorigenic activity. Continued work is needed to explore the benefits of both metformin and Phenformin for the treatment of ovarian cancer and the optimal therapeutic index. Citation Format: Amanda L. Jackson, Joshua E. Kilgore, Haifeng Qiu, Chunxiao Zhou, Paola A. Gehrig, Victoria L. Bae-Jump. Antitumorigenic effects of Phenformin in human ovarian cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2442. doi:10.1158/1538-7445.AM2013-2442
Amanda L Jackson - One of the best experts on this subject based on the ideXlab platform.
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abstract 1313 anti tumorigenic effects of Phenformin in human endometrial cancer cells
Cancer Research, 2014Co-Authors: Amanda L Jackson, Joshua Kilgore, Haifeng Qiu, Chunxiao Zhou, Paola A Gehrig, Victoria L BaejumpAbstract:Introduction: The anti-diabetic drugs, metformin and Phenformin, are thought to have anti-tumorigenic benefits. Preclinical studies suggest that Phenformin may be more potent for inhibiting tumor growth than metformin. Our objective was to assess the anti-tumorigenic effects of Phenformin in endometrial cancer (EC) cell lines and primary cultures. Methods: The EC cell lines, ECC-1 and Ishikawa, were treated with Phenformin under low glucose (2 mM), normal glucose (5.5 mM) and high glucose (25 mM) conditions. EC tumors were collected from consenting patients, at the time of surgical staging for primary culture. Cell proliferation was assessed by MTT assay. Apoptosis was analyzed by Annexin V-FITC assay. Cellometer evaluated cell cycle progression. Invasion was demonstrated by transwell invasion assay. Adhesion was assessed by ELISA. Western blotting was performed to determine expression of the downstream targets of Phenformin. Results: Phenformin inhibited proliferation in a dose-dependent manner in both EC cell lines, within 48-72 hrs of exposure (IC50=1 mM, p=0.0004-0.009). Inhibition of proliferation was seen for all glucose concentrations, but greater potency was observed under low glucose conditions. Treatment with Phenformin resulted in G1 arrest, induction of apoptosis (p=0.022-0.017) and inhibition of adhesion (p=0.0053-0.0144) and invasion (p=0.0063-0.05). Phenformin increased p21 and p27 and decreased cyclin D, cyclin E2, CDK4 and CDK 6, corresponding with G1 arrest. Phenformin significantly inhibited proliferation in 62% (8/13) of the EC primary cultures, within 48-72 hrs of exposure (IC50 0.1-5mM, p=0.00001-0.016). 3 additional EC samples (23%) were significantly inhibited by Phenformin but did not reach an IC50 (p=0.0003-0.018), and 2/13 (15%) had no response to Phenformin. Western blot analysis demonstrated that Phenformin increased phosphorylation of AMPK and decreased phosphorylation of S6 coincident with inhibition of proliferation in the EC cell lines and primary cultures. Conclusion: Phenformin potently inhibited cell growth via G1 arrest and induced apoptosis in EC cell lines and the majority of primary cultures. Inhibition of adhesion/invasion was also seen with Phenformin. Continued work is needed to explore whether Phenformin has superior benefits over metformin. Citation Format: Amanda L. Jackson, Joshua E. Kilgore, Haifeng Qiu, Chunxiao Zhou, Paola A. Gehrig, Victoria L. Bae-Jump. Anti-tumorigenic effects of Phenformin in human endometrial cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1313. doi:10.1158/1538-7445.AM2014-1313
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abstract 3113 Phenformin has anti tumorigenic effects in human ovarian cancer cells and in a genetically engineered mouse model of serous ovarian cancer
Cancer Research, 2014Co-Authors: Amanda L Jackson, Joshua Kilgore, Chunxiao Zhou, Xiaoyun Han, Liza Makowski, Victoria L BaejumpAbstract:Objectives: Anti-diabetic biguanide drugs have been shown to have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Phenformin is a biguanide that is associated with a higher risk of lactic acidosis than is seen in metformin. In vitro and in vivo studies suggest that Phenformin may be more potent for inhibiting tumor growth than metformin. We sought to examine the efficacy of Phenformin in primary cultures of human ovarian cancers (OCs) as well as in a genetically engineered mouse model of serous OC. Methods: Serous OC tumors were collected from consenting patients, at the time of their surgical debulking for primary culture. Cell proliferation was assessed by MTT assay. Apoptosis was evaluated by Annexin V-FITC assay using Cellometer. Effects of Phenformin on phosphorylated-AMPK and -S6 expression was documented by Western immunoblotting. For the in vivo studies, we utilized the KpB++ serous OC mouse model. This is a more aggressive derivative of the K18-gT121+/-; p53fl/fl;Brca1fl/fl (KpB) genetically engineered OC mouse model. The KpB++ mice were treated with placebo or Phenformin (2 mg/kg body weight in drinking water) following tumor onset for one month. Immunohistochemical analysis was performed on the ovarian tumors after treatment with placebo or Phenformin, in regards to Ki-67 expression, cleaved caspase 3 (a marker of apoptosis), phosphorylated AMPK and phosphorylated S6. Individual slides were digitized using the Aperio ScanScope (Aperio Technologies, Vista, CA), and digital images were analyzed using Aperio ImageScope software. Results: Phenformin significantly inhibited cell proliferation in a dose-dependent manner in 100% (7/7) of the primary cultures of ovarian tumors, within 48 to 72 hours of exposure (p=0.00001-0.015, IC50 range of 0.1-5 mM). Treatment with Phenformin resulted in the induction of apoptosis in 71.4% (5/7) of the ovarian tumors. Western immunoblot analysis demonstrated that Phenformin increased phosphorylation of AMPK and decreased phosphorylation of S6. Phenformin significantly inhibited tumor growth in the KpB++ mice (n=8-13 animals per group) by 68% as compared to placebo treated controls, after one month of treatment (p=0.016). As compared to the placebo treated control animals, Phenformin was found to statistically decrease Ki67 staining, inhibit phosphorylated S6 expression and increase both cleaved caspase 3 and phosphorylated AMPK expression (p= 0.01-0.04). Conclusions: In primary culture of human serous OC tumors, Phenformin potently inhibited cell growth and increased apoptotic cell death through AMPK activation and mTOR pathway inhibition. In vivo studies using the KpB++ mouse model found that Phenformin was highly efficacious in inhibiting tumor growth. Although the risk/benefit ratio clearly favors metformin over Phenformin for the treatment of diabetes, this may not hold true for the treatment of cancer. Citation Format: Amanda L. Jackson, Xiaoyun Han, Joshua E. Kilgore, Chunxiao Zhou, Liza Makowski, Victoria Bae-Jump. Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in a genetically engineered mouse model of serous ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3113. doi:10.1158/1538-7445.AM2014-3113
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abstract 2442 antitumorigenic effects of Phenformin in human ovarian cancer cell lines
Cancer Research, 2013Co-Authors: Amanda L Jackson, Joshua Kilgore, Haifeng Qiu, Chunxiao Zhou, Paola A Gehrig, Victoria L BaejumpAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: Anti-diabetic biguanide drugs, such as metformin, have been shown to have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Phenformin is another biguanide with anti-diabetic activity that was withdrawn from the market due to a risk of lactic acidosis that was higher than that seen with metformin. In vitro and in vivo studies suggest that Phenformin may be more potent for inhibiting tumor growth than metformin. Thus, our objective was to assess the effect of Phenformin on proliferation and apoptosis in ovarian cancer cell lines. Methods: Three ovarian cell lines, SKOV3, IGROV1, and HEY, were used. Cell proliferation was assessed by MTT assay after exposure to Phenformin and after exposure to Phenformin under varying glucose levels. Apoptosis was analyzed by Annexin V-FITC assay. Cell cycle progression was evaluated by Cellometer. Western immunoblotting was performed to determine expression of the downstream targets of Phenformin, including AMPK, ribosomal protein S6, cyclin D and E2, cyclin dependent kinase (CDK) 4 and 6, p21 and p27. Inhibition of adhesion by Phenformin was assessed by in vitro adhesion assay. Results: Phenformin potently inhibited proliferation in a dose-dependent manner in all three ovarian cancer cell lines (IC50 = 2.5mM for SKOV3 and HEY, 1mM for IGROV1 at 48 hours) (p = 0.0035 – 0.00001). Inhibition of proliferation was found at normal, low and high glucose concentrations, but greater potency was observed under low glucose concentrations. Treatment with Phenformin resulted in G1 cell cycle arrest and induction of apoptosis. Cellular adhesion was decreased by 14-32% in the ovarian cancer cell lines at a Phenformin dose of 2.5mM (p = 0.009 – 0.0001). Western immunoblot analysis demonstrated that Phenformin induced phosphorylation of AMPK, its immediate downstream mediator, within 18 hours of exposure. In parallel, treatment with Phenformin decreased phosphorylation of the S6 protein, a key target of the mTOR pathway. Phenformin was also found to increase the cell cycle inhibitors, p21 and p27, and decrease cyclin D, cyclin E2, CDK4 and CDK 6, corresponding with G1 arrest in these cell lines. Conclusion: Phenformin potently inhibited ovarian cancer cell growth via G1 arrest and increased apoptosis. Although the risk/benefit ratio clearly favors metformin over Phenformin for the treatment of diabetes, this may not hold true for the treatment of cancer if Phenformin were found to have superior anti-tumorigenic activity. Continued work is needed to explore the benefits of both metformin and Phenformin for the treatment of ovarian cancer and the optimal therapeutic index. Citation Format: Amanda L. Jackson, Joshua E. Kilgore, Haifeng Qiu, Chunxiao Zhou, Paola A. Gehrig, Victoria L. Bae-Jump. Antitumorigenic effects of Phenformin in human ovarian cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2442. doi:10.1158/1538-7445.AM2013-2442
