Two New Faces of Amifostine: Protector from DNA Damage in Normal Cells and Inhibitor of DNA Repair in Cancer Cells
Amifostine protects normal cells from DNA damage induction by ionizing radiation or chemotherapeutics, whereas cancer cells typically remain uninfluenced. While confirming this phenomenon, we have revealed by comet assay and currently the most sensitive method of DNA double strand break (DSB) quanti...
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| Veröffentlicht in: | Journal of medicinal chemistry 2016-04, Vol.59 (7), p.3003-3017 |
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| creator | Hofer, Michal Falk, Martin Komůrková, Denisa Falková, Iva Bačíková, Alena Klejdus, Bořivoj Pagáčová, Eva Štefančíková, Lenka Weiterová, Lenka Angelis, Karel J Kozubek, Stanislav Dušek, Ladislav Galbavý, Štefan |
| description | Amifostine protects normal cells from DNA damage induction by ionizing radiation or chemotherapeutics, whereas cancer cells typically remain uninfluenced. While confirming this phenomenon, we have revealed by comet assay and currently the most sensitive method of DNA double strand break (DSB) quantification (based on γH2AX/53BP1 high-resolution immunofluorescence microscopy) that amifostine treatment supports DSB repair in γ-irradiated normal NHDF fibroblasts but alters it in MCF7 carcinoma cells. These effects follow from the significantly lower activity of alkaline phosphatase measured in MCF7 cells and their supernatants as compared with NHDF fibroblasts. Liquid chromatography–mass spectrometry confirmed that the amifostine conversion to WR-1065 was significantly more intensive in normal NHDF cells than in tumor MCF cells. In conclusion, due to common differences between normal and cancer cells in their abilities to convert amifostine to its active metabolite WR-1065, amifostine may not only protect in multiple ways normal cells from radiation-induced DNA damage but also make cancer cells suffer from DSB repair alteration. |
| doi_str_mv | 10.1021/acs.jmedchem.5b01628 |
| format | Article |
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While confirming this phenomenon, we have revealed by comet assay and currently the most sensitive method of DNA double strand break (DSB) quantification (based on γH2AX/53BP1 high-resolution immunofluorescence microscopy) that amifostine treatment supports DSB repair in γ-irradiated normal NHDF fibroblasts but alters it in MCF7 carcinoma cells. These effects follow from the significantly lower activity of alkaline phosphatase measured in MCF7 cells and their supernatants as compared with NHDF fibroblasts. Liquid chromatography–mass spectrometry confirmed that the amifostine conversion to WR-1065 was significantly more intensive in normal NHDF cells than in tumor MCF cells. In conclusion, due to common differences between normal and cancer cells in their abilities to convert amifostine to its active metabolite WR-1065, amifostine may not only protect in multiple ways normal cells from radiation-induced DNA damage but also make cancer cells suffer from DSB repair alteration.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.5b01628</identifier><identifier>PMID: 26978566</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Alkaline Phosphatase - genetics ; Alkaline Phosphatase - metabolism ; Amifostine - pharmacokinetics ; Amifostine - pharmacology ; Comet Assay ; DNA Breaks, Double-Stranded - drug effects ; DNA Damage - drug effects ; DNA Repair - drug effects ; Fibroblasts - drug effects ; Fibroblasts - radiation effects ; Gamma Rays ; Histones - genetics ; Histones - metabolism ; Humans ; Intracellular Signaling Peptides and Proteins - genetics ; Intracellular Signaling Peptides and Proteins - metabolism ; MCF-7 Cells - drug effects ; MCF-7 Cells - radiation effects ; Mercaptoethylamines - pharmacokinetics ; Microscopy, Fluorescence - methods ; Radiation-Protective Agents - pharmacology ; Tumor Suppressor p53-Binding Protein 1</subject><ispartof>Journal of medicinal chemistry, 2016-04, Vol.59 (7), p.3003-3017</ispartof><rights>Copyright © 2016 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a414t-8dd7d64250eda5bbef109b7e3bd2768ee46ac3c6aab4052026853e2cbf51b7413</citedby><cites>FETCH-LOGICAL-a414t-8dd7d64250eda5bbef109b7e3bd2768ee46ac3c6aab4052026853e2cbf51b7413</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.5b01628$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01628$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26978566$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hofer, Michal</creatorcontrib><creatorcontrib>Falk, Martin</creatorcontrib><creatorcontrib>Komůrková, Denisa</creatorcontrib><creatorcontrib>Falková, Iva</creatorcontrib><creatorcontrib>Bačíková, Alena</creatorcontrib><creatorcontrib>Klejdus, Bořivoj</creatorcontrib><creatorcontrib>Pagáčová, Eva</creatorcontrib><creatorcontrib>Štefančíková, Lenka</creatorcontrib><creatorcontrib>Weiterová, Lenka</creatorcontrib><creatorcontrib>Angelis, Karel J</creatorcontrib><creatorcontrib>Kozubek, Stanislav</creatorcontrib><creatorcontrib>Dušek, Ladislav</creatorcontrib><creatorcontrib>Galbavý, Štefan</creatorcontrib><title>Two New Faces of Amifostine: Protector from DNA Damage in Normal Cells and Inhibitor of DNA Repair in Cancer Cells</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Amifostine protects normal cells from DNA damage induction by ionizing radiation or chemotherapeutics, whereas cancer cells typically remain uninfluenced. While confirming this phenomenon, we have revealed by comet assay and currently the most sensitive method of DNA double strand break (DSB) quantification (based on γH2AX/53BP1 high-resolution immunofluorescence microscopy) that amifostine treatment supports DSB repair in γ-irradiated normal NHDF fibroblasts but alters it in MCF7 carcinoma cells. These effects follow from the significantly lower activity of alkaline phosphatase measured in MCF7 cells and their supernatants as compared with NHDF fibroblasts. Liquid chromatography–mass spectrometry confirmed that the amifostine conversion to WR-1065 was significantly more intensive in normal NHDF cells than in tumor MCF cells. In conclusion, due to common differences between normal and cancer cells in their abilities to convert amifostine to its active metabolite WR-1065, amifostine may not only protect in multiple ways normal cells from radiation-induced DNA damage but also make cancer cells suffer from DSB repair alteration.</description><subject>Alkaline Phosphatase - genetics</subject><subject>Alkaline Phosphatase - metabolism</subject><subject>Amifostine - pharmacokinetics</subject><subject>Amifostine - pharmacology</subject><subject>Comet Assay</subject><subject>DNA Breaks, Double-Stranded - drug effects</subject><subject>DNA Damage - drug effects</subject><subject>DNA Repair - drug effects</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - radiation effects</subject><subject>Gamma Rays</subject><subject>Histones - genetics</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins - genetics</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>MCF-7 Cells - drug effects</subject><subject>MCF-7 Cells - radiation effects</subject><subject>Mercaptoethylamines - pharmacokinetics</subject><subject>Microscopy, Fluorescence - methods</subject><subject>Radiation-Protective Agents - pharmacology</subject><subject>Tumor Suppressor p53-Binding Protein 1</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kNFOwjAUhhujEUTfwJi-wPC067rhHRmiJASNweul7c5kZFtJCyG-vZsDL706F-f7_-T_CLlnMGbA2aMyfrytMTcbrMeRBiZ5ckGGLOIQiATEJRkCcB5wycMBufF-CwAh4-E1GXA5iZNIyiFx66OlKzzSuTLoqS3otC4L6_dlg0_03dk9mr11tHC2prPVlM5Urb6Qlg1dWVeriqZYVZ6qJqeLZlPqsqPbmo79wJ0qXcemqjHoevaWXBWq8nh3uiPyOX9ep6_B8u1lkU6XgRJM7IMkz-NcCh4B5irSGgsGEx1jqHMeywRRSGVCI5XSAtrRXCZRiNzoImI6FiwcEdH3Gme9d1hkO1fWyn1nDLJOYdYqzM4Ks5PCNvbQx3YH3f7-QmdnLQA98Bu3B9e0K_7v_AFq3oAT</recordid><startdate>20160414</startdate><enddate>20160414</enddate><creator>Hofer, Michal</creator><creator>Falk, Martin</creator><creator>Komůrková, Denisa</creator><creator>Falková, Iva</creator><creator>Bačíková, Alena</creator><creator>Klejdus, Bořivoj</creator><creator>Pagáčová, Eva</creator><creator>Štefančíková, Lenka</creator><creator>Weiterová, Lenka</creator><creator>Angelis, Karel J</creator><creator>Kozubek, Stanislav</creator><creator>Dušek, Ladislav</creator><creator>Galbavý, Štefan</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20160414</creationdate><title>Two New Faces of Amifostine: Protector from DNA Damage in Normal Cells and Inhibitor of DNA Repair in Cancer Cells</title><author>Hofer, Michal ; Falk, Martin ; Komůrková, Denisa ; Falková, Iva ; Bačíková, Alena ; Klejdus, Bořivoj ; Pagáčová, Eva ; Štefančíková, Lenka ; Weiterová, Lenka ; Angelis, Karel J ; Kozubek, Stanislav ; Dušek, Ladislav ; Galbavý, Štefan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a414t-8dd7d64250eda5bbef109b7e3bd2768ee46ac3c6aab4052026853e2cbf51b7413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Alkaline Phosphatase - genetics</topic><topic>Alkaline Phosphatase - metabolism</topic><topic>Amifostine - pharmacokinetics</topic><topic>Amifostine - pharmacology</topic><topic>Comet Assay</topic><topic>DNA Breaks, Double-Stranded - drug effects</topic><topic>DNA Damage - drug effects</topic><topic>DNA Repair - drug effects</topic><topic>Fibroblasts - drug effects</topic><topic>Fibroblasts - radiation effects</topic><topic>Gamma Rays</topic><topic>Histones - genetics</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins - genetics</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>MCF-7 Cells - drug effects</topic><topic>MCF-7 Cells - radiation effects</topic><topic>Mercaptoethylamines - pharmacokinetics</topic><topic>Microscopy, Fluorescence - methods</topic><topic>Radiation-Protective Agents - pharmacology</topic><topic>Tumor Suppressor p53-Binding Protein 1</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hofer, Michal</creatorcontrib><creatorcontrib>Falk, Martin</creatorcontrib><creatorcontrib>Komůrková, Denisa</creatorcontrib><creatorcontrib>Falková, Iva</creatorcontrib><creatorcontrib>Bačíková, Alena</creatorcontrib><creatorcontrib>Klejdus, Bořivoj</creatorcontrib><creatorcontrib>Pagáčová, Eva</creatorcontrib><creatorcontrib>Štefančíková, Lenka</creatorcontrib><creatorcontrib>Weiterová, Lenka</creatorcontrib><creatorcontrib>Angelis, Karel J</creatorcontrib><creatorcontrib>Kozubek, Stanislav</creatorcontrib><creatorcontrib>Dušek, Ladislav</creatorcontrib><creatorcontrib>Galbavý, Štefan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hofer, Michal</au><au>Falk, Martin</au><au>Komůrková, Denisa</au><au>Falková, Iva</au><au>Bačíková, Alena</au><au>Klejdus, Bořivoj</au><au>Pagáčová, Eva</au><au>Štefančíková, Lenka</au><au>Weiterová, Lenka</au><au>Angelis, Karel J</au><au>Kozubek, Stanislav</au><au>Dušek, Ladislav</au><au>Galbavý, Štefan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Two New Faces of Amifostine: Protector from DNA Damage in Normal Cells and Inhibitor of DNA Repair in Cancer Cells</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2016-04-14</date><risdate>2016</risdate><volume>59</volume><issue>7</issue><spage>3003</spage><epage>3017</epage><pages>3003-3017</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Amifostine protects normal cells from DNA damage induction by ionizing radiation or chemotherapeutics, whereas cancer cells typically remain uninfluenced. While confirming this phenomenon, we have revealed by comet assay and currently the most sensitive method of DNA double strand break (DSB) quantification (based on γH2AX/53BP1 high-resolution immunofluorescence microscopy) that amifostine treatment supports DSB repair in γ-irradiated normal NHDF fibroblasts but alters it in MCF7 carcinoma cells. These effects follow from the significantly lower activity of alkaline phosphatase measured in MCF7 cells and their supernatants as compared with NHDF fibroblasts. Liquid chromatography–mass spectrometry confirmed that the amifostine conversion to WR-1065 was significantly more intensive in normal NHDF cells than in tumor MCF cells. In conclusion, due to common differences between normal and cancer cells in their abilities to convert amifostine to its active metabolite WR-1065, amifostine may not only protect in multiple ways normal cells from radiation-induced DNA damage but also make cancer cells suffer from DSB repair alteration.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>26978566</pmid><doi>10.1021/acs.jmedchem.5b01628</doi><tpages>15</tpages></addata></record> |
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| source | ACS Publications; MEDLINE |
| subjects | Alkaline Phosphatase - genetics Alkaline Phosphatase - metabolism Amifostine - pharmacokinetics Amifostine - pharmacology Comet Assay DNA Breaks, Double-Stranded - drug effects DNA Damage - drug effects DNA Repair - drug effects Fibroblasts - drug effects Fibroblasts - radiation effects Gamma Rays Histones - genetics Histones - metabolism Humans Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism MCF-7 Cells - drug effects MCF-7 Cells - radiation effects Mercaptoethylamines - pharmacokinetics Microscopy, Fluorescence - methods Radiation-Protective Agents - pharmacology Tumor Suppressor p53-Binding Protein 1 |
| title | Two New Faces of Amifostine: Protector from DNA Damage in Normal Cells and Inhibitor of DNA Repair in Cancer Cells |
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