Metformin plus sorafenib highly impacts temozolomide resistant glioblastoma stem-like cells
Glioblastoma stem cells (GSCs), responsible for the dismal disease prognosis after conventional treatments, are driven by overactive signaling pathways, such as PI3K/ AKT/mTOR and RAS/RAF/MAPK. The objective of our study was to target in vitro-GSCs by combining metformin (Met) as a mTOR inhibitor, w...
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| Veröffentlicht in: | Journal of B.U. ON. 2014-04, Vol.19 (2), p.502-511 |
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| creator | Aldea, Mihaela D Petrushev, Bobe Soritau, Olga Tomuleasa, Ciprian I Berindan-Neagoe, Ioana Filip, Adriana G Chereches, Gabriela Cenariu, Mihai Craciun, Lucian Tatomir, Corina Florian, Ioan-Stefan Crivii, Carmen B Kacso, Gabriel |
| description | Glioblastoma stem cells (GSCs), responsible for the dismal disease prognosis after conventional treatments, are driven by overactive signaling pathways, such as PI3K/ AKT/mTOR and RAS/RAF/MAPK. The objective of our study was to target in vitro-GSCs by combining metformin (Met) as a mTOR inhibitor, with sorafenib (Soraf) as a RAF inhibitor.
GSCs cultured under basal conditions were treated with Met, temozolomide (TMZ), Soraf, Met+TMZ and Met+Soraf; as untreated arm served as control. At 4 hrs of drug exposure, we measured the level of reactive oxygen species (ROS) by 2',7'-dichlorofluorescein diacetate (DCFDA) assay, apoptosis by prodium iodide (PI)-V Annexin staining and efflux pump activity by using the fluorescent dye rhodamine 123. At 24 hrs, we measured cell proliferation by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, apoptosis and malondialdehyde (MDA) levels. MTT results were compared with corresponding measurements on cultures of non-stem glioblastoma cells and osteoblasts.
Met+Soraf exerted the highest antiproliferative effects in GSCs and non-stem glioblastoma cells (p |
| format | Article |
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GSCs cultured under basal conditions were treated with Met, temozolomide (TMZ), Soraf, Met+TMZ and Met+Soraf; as untreated arm served as control. At 4 hrs of drug exposure, we measured the level of reactive oxygen species (ROS) by 2',7'-dichlorofluorescein diacetate (DCFDA) assay, apoptosis by prodium iodide (PI)-V Annexin staining and efflux pump activity by using the fluorescent dye rhodamine 123. At 24 hrs, we measured cell proliferation by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, apoptosis and malondialdehyde (MDA) levels. MTT results were compared with corresponding measurements on cultures of non-stem glioblastoma cells and osteoblasts.
Met+Soraf exerted the highest antiproliferative effects in GSCs and non-stem glioblastoma cells (p<0.001). Both Met and Soraf monotherapy exhibited a selective cytotoxic effect on GSCs (p<0.001), while no effect was detected on non-stem glioblastoma cells (p>0.05). Soraf, but not Met, impacted the proliferation of normal cells. Soraf displayed synergism with Met in producing high levels of ROS, decreasing efflux pump activity and generating the highest apoptotic rates when compared to either drug alone (p<0.001).
GSCs were highly sensitive to the combination of Met and Soraf which reduced cell proliferation, increased oxidative stress, inhibited efflux pump activity and ultimately killed GSCs. We strongly believe that these results warrant further in vivo exploration.</description><identifier>ISSN: 1107-0625</identifier><identifier>PMID: 24965413</identifier><language>eng</language><publisher>Greece</publisher><subject><![CDATA[Apoptosis - drug effects ; Brain Neoplasms - drug therapy ; Brain Neoplasms - pathology ; Dacarbazine - analogs & derivatives ; Dacarbazine - therapeutic use ; Drug Resistance, Neoplasm ; Glioblastoma - drug therapy ; Glioblastoma - pathology ; Humans ; Lipid Peroxidation ; Metformin - administration & dosage ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - metabolism ; Niacinamide - administration & dosage ; Niacinamide - analogs & derivatives ; Oxidative Stress ; Phenylurea Compounds - administration & dosage ; raf Kinases - antagonists & inhibitors ; Rhodamine 123 - metabolism ; TOR Serine-Threonine Kinases - antagonists & inhibitors]]></subject><ispartof>Journal of B.U. ON., 2014-04, Vol.19 (2), p.502-511</ispartof><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24965413$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Aldea, Mihaela D</creatorcontrib><creatorcontrib>Petrushev, Bobe</creatorcontrib><creatorcontrib>Soritau, Olga</creatorcontrib><creatorcontrib>Tomuleasa, Ciprian I</creatorcontrib><creatorcontrib>Berindan-Neagoe, Ioana</creatorcontrib><creatorcontrib>Filip, Adriana G</creatorcontrib><creatorcontrib>Chereches, Gabriela</creatorcontrib><creatorcontrib>Cenariu, Mihai</creatorcontrib><creatorcontrib>Craciun, Lucian</creatorcontrib><creatorcontrib>Tatomir, Corina</creatorcontrib><creatorcontrib>Florian, Ioan-Stefan</creatorcontrib><creatorcontrib>Crivii, Carmen B</creatorcontrib><creatorcontrib>Kacso, Gabriel</creatorcontrib><title>Metformin plus sorafenib highly impacts temozolomide resistant glioblastoma stem-like cells</title><title>Journal of B.U. ON.</title><addtitle>J BUON</addtitle><description>Glioblastoma stem cells (GSCs), responsible for the dismal disease prognosis after conventional treatments, are driven by overactive signaling pathways, such as PI3K/ AKT/mTOR and RAS/RAF/MAPK. The objective of our study was to target in vitro-GSCs by combining metformin (Met) as a mTOR inhibitor, with sorafenib (Soraf) as a RAF inhibitor.
GSCs cultured under basal conditions were treated with Met, temozolomide (TMZ), Soraf, Met+TMZ and Met+Soraf; as untreated arm served as control. At 4 hrs of drug exposure, we measured the level of reactive oxygen species (ROS) by 2',7'-dichlorofluorescein diacetate (DCFDA) assay, apoptosis by prodium iodide (PI)-V Annexin staining and efflux pump activity by using the fluorescent dye rhodamine 123. At 24 hrs, we measured cell proliferation by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, apoptosis and malondialdehyde (MDA) levels. MTT results were compared with corresponding measurements on cultures of non-stem glioblastoma cells and osteoblasts.
Met+Soraf exerted the highest antiproliferative effects in GSCs and non-stem glioblastoma cells (p<0.001). Both Met and Soraf monotherapy exhibited a selective cytotoxic effect on GSCs (p<0.001), while no effect was detected on non-stem glioblastoma cells (p>0.05). Soraf, but not Met, impacted the proliferation of normal cells. Soraf displayed synergism with Met in producing high levels of ROS, decreasing efflux pump activity and generating the highest apoptotic rates when compared to either drug alone (p<0.001).
GSCs were highly sensitive to the combination of Met and Soraf which reduced cell proliferation, increased oxidative stress, inhibited efflux pump activity and ultimately killed GSCs. We strongly believe that these results warrant further in vivo exploration.</description><subject>Apoptosis - drug effects</subject><subject>Brain Neoplasms - drug therapy</subject><subject>Brain Neoplasms - pathology</subject><subject>Dacarbazine - analogs & derivatives</subject><subject>Dacarbazine - therapeutic use</subject><subject>Drug Resistance, Neoplasm</subject><subject>Glioblastoma - drug therapy</subject><subject>Glioblastoma - pathology</subject><subject>Humans</subject><subject>Lipid Peroxidation</subject><subject>Metformin - administration & dosage</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Niacinamide - administration & dosage</subject><subject>Niacinamide - analogs & derivatives</subject><subject>Oxidative Stress</subject><subject>Phenylurea Compounds - administration & dosage</subject><subject>raf Kinases - antagonists & inhibitors</subject><subject>Rhodamine 123 - metabolism</subject><subject>TOR Serine-Threonine Kinases - antagonists & inhibitors</subject><issn>1107-0625</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kD1PwzAYhD2AaFX6F5BHlkj-SJx4RBVfUhELTAyR7bxpDXYc8jpD-fW0otxyy6PT3V2QJeesLpgS1YKsET_ZUYpxpZsrshClVlXJ5ZJ8vEDu0xT9QMcwI8U0mR4Gb-ne7_bhQH0cjctIM8T0k0KKvgM6AXrMZsh0F3yywWBO0VA8QkXwX0AdhIDX5LI3AWF99hV5f7h_2zwV29fH583dthgF57lowHVCO-k0KMmF6owRtmm4BSO1hVI4JirNNK-NdkzKsuZQSitk55S0pZErcvuXO07pewbMbfR4amAGSDO2_DRVaVlVR_TmjM42QteOk49mOrT_h8hf9C1dzw</recordid><startdate>20140401</startdate><enddate>20140401</enddate><creator>Aldea, Mihaela D</creator><creator>Petrushev, Bobe</creator><creator>Soritau, Olga</creator><creator>Tomuleasa, Ciprian I</creator><creator>Berindan-Neagoe, Ioana</creator><creator>Filip, Adriana G</creator><creator>Chereches, Gabriela</creator><creator>Cenariu, Mihai</creator><creator>Craciun, Lucian</creator><creator>Tatomir, Corina</creator><creator>Florian, Ioan-Stefan</creator><creator>Crivii, Carmen B</creator><creator>Kacso, Gabriel</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20140401</creationdate><title>Metformin plus sorafenib highly impacts temozolomide resistant glioblastoma stem-like cells</title><author>Aldea, Mihaela D ; Petrushev, Bobe ; Soritau, Olga ; Tomuleasa, Ciprian I ; Berindan-Neagoe, Ioana ; Filip, Adriana G ; Chereches, Gabriela ; Cenariu, Mihai ; Craciun, Lucian ; Tatomir, Corina ; Florian, Ioan-Stefan ; Crivii, Carmen B ; Kacso, Gabriel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p211t-8ecd29c3c9e63126daa2b881bea39be42c02590917a9c033471e43b23dc63b4a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Apoptosis - drug effects</topic><topic>Brain Neoplasms - drug therapy</topic><topic>Brain Neoplasms - pathology</topic><topic>Dacarbazine - analogs & derivatives</topic><topic>Dacarbazine - therapeutic use</topic><topic>Drug Resistance, Neoplasm</topic><topic>Glioblastoma - drug therapy</topic><topic>Glioblastoma - pathology</topic><topic>Humans</topic><topic>Lipid Peroxidation</topic><topic>Metformin - administration & dosage</topic><topic>Neoplastic Stem Cells - drug effects</topic><topic>Neoplastic Stem Cells - metabolism</topic><topic>Niacinamide - administration & dosage</topic><topic>Niacinamide - analogs & derivatives</topic><topic>Oxidative Stress</topic><topic>Phenylurea Compounds - administration & dosage</topic><topic>raf Kinases - antagonists & inhibitors</topic><topic>Rhodamine 123 - metabolism</topic><topic>TOR Serine-Threonine Kinases - antagonists & inhibitors</topic><toplevel>online_resources</toplevel><creatorcontrib>Aldea, Mihaela D</creatorcontrib><creatorcontrib>Petrushev, Bobe</creatorcontrib><creatorcontrib>Soritau, Olga</creatorcontrib><creatorcontrib>Tomuleasa, Ciprian I</creatorcontrib><creatorcontrib>Berindan-Neagoe, Ioana</creatorcontrib><creatorcontrib>Filip, Adriana G</creatorcontrib><creatorcontrib>Chereches, Gabriela</creatorcontrib><creatorcontrib>Cenariu, Mihai</creatorcontrib><creatorcontrib>Craciun, Lucian</creatorcontrib><creatorcontrib>Tatomir, Corina</creatorcontrib><creatorcontrib>Florian, Ioan-Stefan</creatorcontrib><creatorcontrib>Crivii, Carmen B</creatorcontrib><creatorcontrib>Kacso, Gabriel</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of B.U. ON.</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Aldea, Mihaela D</au><au>Petrushev, Bobe</au><au>Soritau, Olga</au><au>Tomuleasa, Ciprian I</au><au>Berindan-Neagoe, Ioana</au><au>Filip, Adriana G</au><au>Chereches, Gabriela</au><au>Cenariu, Mihai</au><au>Craciun, Lucian</au><au>Tatomir, Corina</au><au>Florian, Ioan-Stefan</au><au>Crivii, Carmen B</au><au>Kacso, Gabriel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Metformin plus sorafenib highly impacts temozolomide resistant glioblastoma stem-like cells</atitle><jtitle>Journal of B.U. ON.</jtitle><addtitle>J BUON</addtitle><date>2014-04-01</date><risdate>2014</risdate><volume>19</volume><issue>2</issue><spage>502</spage><epage>511</epage><pages>502-511</pages><issn>1107-0625</issn><abstract>Glioblastoma stem cells (GSCs), responsible for the dismal disease prognosis after conventional treatments, are driven by overactive signaling pathways, such as PI3K/ AKT/mTOR and RAS/RAF/MAPK. The objective of our study was to target in vitro-GSCs by combining metformin (Met) as a mTOR inhibitor, with sorafenib (Soraf) as a RAF inhibitor.
GSCs cultured under basal conditions were treated with Met, temozolomide (TMZ), Soraf, Met+TMZ and Met+Soraf; as untreated arm served as control. At 4 hrs of drug exposure, we measured the level of reactive oxygen species (ROS) by 2',7'-dichlorofluorescein diacetate (DCFDA) assay, apoptosis by prodium iodide (PI)-V Annexin staining and efflux pump activity by using the fluorescent dye rhodamine 123. At 24 hrs, we measured cell proliferation by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, apoptosis and malondialdehyde (MDA) levels. MTT results were compared with corresponding measurements on cultures of non-stem glioblastoma cells and osteoblasts.
Met+Soraf exerted the highest antiproliferative effects in GSCs and non-stem glioblastoma cells (p<0.001). Both Met and Soraf monotherapy exhibited a selective cytotoxic effect on GSCs (p<0.001), while no effect was detected on non-stem glioblastoma cells (p>0.05). Soraf, but not Met, impacted the proliferation of normal cells. Soraf displayed synergism with Met in producing high levels of ROS, decreasing efflux pump activity and generating the highest apoptotic rates when compared to either drug alone (p<0.001).
GSCs were highly sensitive to the combination of Met and Soraf which reduced cell proliferation, increased oxidative stress, inhibited efflux pump activity and ultimately killed GSCs. We strongly believe that these results warrant further in vivo exploration.</abstract><cop>Greece</cop><pmid>24965413</pmid><tpages>10</tpages></addata></record> |
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| subjects | Apoptosis - drug effects Brain Neoplasms - drug therapy Brain Neoplasms - pathology Dacarbazine - analogs & derivatives Dacarbazine - therapeutic use Drug Resistance, Neoplasm Glioblastoma - drug therapy Glioblastoma - pathology Humans Lipid Peroxidation Metformin - administration & dosage Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Niacinamide - administration & dosage Niacinamide - analogs & derivatives Oxidative Stress Phenylurea Compounds - administration & dosage raf Kinases - antagonists & inhibitors Rhodamine 123 - metabolism TOR Serine-Threonine Kinases - antagonists & inhibitors |
| title | Metformin plus sorafenib highly impacts temozolomide resistant glioblastoma stem-like cells |
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