Zebularine induces chemosensitization to methotrexate and efficiently decreases AhR gene methylation in childhood acute lymphoblastic leukemia cells
Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in childhood. Despite the advances in treatment, about 20% of patients relapse and/or die, indicating the need for different therapies for this group. Zebularine (ZB) is a potent DNA methyltransferase (DNMT) inhibitor and h...
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| Veröffentlicht in: | Anti-cancer drugs 2014-01, Vol.25 (1), p.72-81 |
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| creator | Andrade, Augusto F Borges, Kleiton S Castro-Gamero, Angel M Silveira, Vanessa S Suazo, Veridiana K Oliveira, Jaqueline C Moreno, Daniel A de Paula Queiroz, Rosane G Scrideli, Carlos A Tone, Luiz G |
| description | Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in childhood. Despite the advances in treatment, about 20% of patients relapse and/or die, indicating the need for different therapies for this group. Zebularine (ZB) is a potent DNA methyltransferase (DNMT) inhibitor and has been associated with gene demethylation and enhancement of tumor chemosensitivity. This study aimed to evaluate the effects of ZB, alone or combined with chemotherapeutics (methotrexate and vincristine), on childhood ALL cell lines. Cell proliferation, apoptosis, and clonogenic capacity were studied in Jurkat and ReH cell lines. Bisulfite modification, followed by methylation-specific PCR was carried out to evaluate aryl hydrocarbon receptor (AhR) methylation status. Gene expression of DNMT1, DNMT3a, DNMT3b, and AhR was assessed using qRT-PCR. Both cell cultures were sensitive to ZB, showing a dose-dependent and time-dependent response (P |
| doi_str_mv | 10.1097/CAD.0000000000000028 |
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Despite the advances in treatment, about 20% of patients relapse and/or die, indicating the need for different therapies for this group. Zebularine (ZB) is a potent DNA methyltransferase (DNMT) inhibitor and has been associated with gene demethylation and enhancement of tumor chemosensitivity. This study aimed to evaluate the effects of ZB, alone or combined with chemotherapeutics (methotrexate and vincristine), on childhood ALL cell lines. Cell proliferation, apoptosis, and clonogenic capacity were studied in Jurkat and ReH cell lines. Bisulfite modification, followed by methylation-specific PCR was carried out to evaluate aryl hydrocarbon receptor (AhR) methylation status. Gene expression of DNMT1, DNMT3a, DNMT3b, and AhR was assessed using qRT-PCR. Both cell cultures were sensitive to ZB, showing a dose-dependent and time-dependent response (P<0.05). ZB induced apoptosis and decreased clonogenic capacity in both cell lines. Combination with methotrexate resulted in a strong synergistic effect, whereas combination with vincristine led to an antagonistic response in both cell lines. ZB treatment decreased gene expression of the three DNMTs and induced AhR gene promoter demethylation and its re-expression. These results indicate that ZB may be a promising drug for the adjuvant treatment of ALL, mainly when combined with methotrexate.</description><identifier>ISSN: 0959-4973</identifier><identifier>EISSN: 1473-5741</identifier><identifier>DOI: 10.1097/CAD.0000000000000028</identifier><identifier>PMID: 24052107</identifier><language>eng</language><publisher>England: Wolters Kluwer Health | Lippincott Williams & Wilkins</publisher><subject>Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Basic Helix-Loop-Helix Transcription Factors - genetics ; Basic Helix-Loop-Helix Transcription Factors - metabolism ; Cell Line, Tumor ; Cytidine - analogs & derivatives ; Cytidine - pharmacology ; DNA Modification Methylases - antagonists & inhibitors ; Drug Antagonism ; Drug Resistance, Neoplasm ; Drug Synergism ; Humans ; Methotrexate - pharmacology ; Methylation ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism ; Receptors, Aryl Hydrocarbon - genetics ; Receptors, Aryl Hydrocarbon - metabolism ; Vincristine - pharmacology</subject><ispartof>Anti-cancer drugs, 2014-01, Vol.25 (1), p.72-81</ispartof><rights>2014 Wolters Kluwer Health | Lippincott Williams & Wilkins</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5018-17f4ceda3a2ba04fced90011fe6a78d133831c7c0b092b3e408f420a18d256ee3</citedby><cites>FETCH-LOGICAL-c5018-17f4ceda3a2ba04fced90011fe6a78d133831c7c0b092b3e408f420a18d256ee3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24052107$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Andrade, Augusto F</creatorcontrib><creatorcontrib>Borges, Kleiton S</creatorcontrib><creatorcontrib>Castro-Gamero, Angel M</creatorcontrib><creatorcontrib>Silveira, Vanessa S</creatorcontrib><creatorcontrib>Suazo, Veridiana K</creatorcontrib><creatorcontrib>Oliveira, Jaqueline C</creatorcontrib><creatorcontrib>Moreno, Daniel A</creatorcontrib><creatorcontrib>de Paula Queiroz, Rosane G</creatorcontrib><creatorcontrib>Scrideli, Carlos A</creatorcontrib><creatorcontrib>Tone, Luiz G</creatorcontrib><title>Zebularine induces chemosensitization to methotrexate and efficiently decreases AhR gene methylation in childhood acute lymphoblastic leukemia cells</title><title>Anti-cancer drugs</title><addtitle>Anticancer Drugs</addtitle><description>Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in childhood. Despite the advances in treatment, about 20% of patients relapse and/or die, indicating the need for different therapies for this group. Zebularine (ZB) is a potent DNA methyltransferase (DNMT) inhibitor and has been associated with gene demethylation and enhancement of tumor chemosensitivity. This study aimed to evaluate the effects of ZB, alone or combined with chemotherapeutics (methotrexate and vincristine), on childhood ALL cell lines. Cell proliferation, apoptosis, and clonogenic capacity were studied in Jurkat and ReH cell lines. Bisulfite modification, followed by methylation-specific PCR was carried out to evaluate aryl hydrocarbon receptor (AhR) methylation status. Gene expression of DNMT1, DNMT3a, DNMT3b, and AhR was assessed using qRT-PCR. Both cell cultures were sensitive to ZB, showing a dose-dependent and time-dependent response (P<0.05). ZB induced apoptosis and decreased clonogenic capacity in both cell lines. Combination with methotrexate resulted in a strong synergistic effect, whereas combination with vincristine led to an antagonistic response in both cell lines. ZB treatment decreased gene expression of the three DNMTs and induced AhR gene promoter demethylation and its re-expression. These results indicate that ZB may be a promising drug for the adjuvant treatment of ALL, mainly when combined with methotrexate.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Basic Helix-Loop-Helix Transcription Factors - genetics</subject><subject>Basic Helix-Loop-Helix Transcription Factors - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cytidine - analogs & derivatives</subject><subject>Cytidine - pharmacology</subject><subject>DNA Modification Methylases - antagonists & inhibitors</subject><subject>Drug Antagonism</subject><subject>Drug Resistance, Neoplasm</subject><subject>Drug Synergism</subject><subject>Humans</subject><subject>Methotrexate - pharmacology</subject><subject>Methylation</subject><subject>Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism</subject><subject>Receptors, Aryl Hydrocarbon - genetics</subject><subject>Receptors, Aryl Hydrocarbon - metabolism</subject><subject>Vincristine - pharmacology</subject><issn>0959-4973</issn><issn>1473-5741</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUFvFCEYhomxsdvqPzCGo5epMDDLcNys1Zo0adLoxcvkG_jGwTLDCkzq-jv6g2Wz1UQPygVCnvf5CC8hLzm74EyrN9vN2wv2x6rbJ2TFpRJVoyR_SlZMN7qSWolTcpbS14KUe_GMnNaSNTVnakUePmO_eIhuRupmuxhM1Iw4hYRzctn9gOzCTHOgE-Yx5IjfISOF2VIcBmccztnvqUUTEVIJb8Zb-gWL7cDv_THu5iJ13o4hWApmKQa_n3Zj6D2k7Az1uNzh5IAa9D49JycD-IQvHvdz8und5cftVXV98_7DdnNdmYbxtuJqkAYtCKh7YHIoZ80Y5wOuQbWWC9EKbpRhPdN1L1CydpA1A97aulkjinPy-ujdxfBtwZS7yaXDC2DGsKSON7XW5Z-4-j8q12We0u26oPKImhhSijh0u-gmiPuOs-5QXVeq6_6ursRePU5Y-gnt79CvrgrQHoH74DPGdOeXe4zdiODz-G_3T6xIqH8</recordid><startdate>201401</startdate><enddate>201401</enddate><creator>Andrade, Augusto F</creator><creator>Borges, Kleiton S</creator><creator>Castro-Gamero, Angel M</creator><creator>Silveira, Vanessa S</creator><creator>Suazo, Veridiana K</creator><creator>Oliveira, Jaqueline C</creator><creator>Moreno, Daniel A</creator><creator>de Paula Queiroz, Rosane G</creator><creator>Scrideli, Carlos A</creator><creator>Tone, Luiz G</creator><general>Wolters Kluwer Health | Lippincott Williams & Wilkins</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><scope>7X8</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>201401</creationdate><title>Zebularine induces chemosensitization to methotrexate and efficiently decreases AhR gene methylation in childhood acute lymphoblastic leukemia cells</title><author>Andrade, Augusto F ; Borges, Kleiton S ; Castro-Gamero, Angel M ; Silveira, Vanessa S ; Suazo, Veridiana K ; Oliveira, Jaqueline C ; Moreno, Daniel A ; de Paula Queiroz, Rosane G ; Scrideli, Carlos A ; Tone, Luiz G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5018-17f4ceda3a2ba04fced90011fe6a78d133831c7c0b092b3e408f420a18d256ee3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Basic Helix-Loop-Helix Transcription Factors - genetics</topic><topic>Basic Helix-Loop-Helix Transcription Factors - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cytidine - analogs & derivatives</topic><topic>Cytidine - pharmacology</topic><topic>DNA Modification Methylases - antagonists & inhibitors</topic><topic>Drug Antagonism</topic><topic>Drug Resistance, Neoplasm</topic><topic>Drug Synergism</topic><topic>Humans</topic><topic>Methotrexate - pharmacology</topic><topic>Methylation</topic><topic>Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism</topic><topic>Receptors, Aryl Hydrocarbon - genetics</topic><topic>Receptors, Aryl Hydrocarbon - metabolism</topic><topic>Vincristine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Andrade, Augusto F</creatorcontrib><creatorcontrib>Borges, Kleiton S</creatorcontrib><creatorcontrib>Castro-Gamero, Angel M</creatorcontrib><creatorcontrib>Silveira, Vanessa S</creatorcontrib><creatorcontrib>Suazo, Veridiana K</creatorcontrib><creatorcontrib>Oliveira, Jaqueline C</creatorcontrib><creatorcontrib>Moreno, Daniel A</creatorcontrib><creatorcontrib>de Paula Queiroz, Rosane G</creatorcontrib><creatorcontrib>Scrideli, Carlos A</creatorcontrib><creatorcontrib>Tone, Luiz G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Anti-cancer drugs</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Andrade, Augusto F</au><au>Borges, Kleiton S</au><au>Castro-Gamero, Angel M</au><au>Silveira, Vanessa S</au><au>Suazo, Veridiana K</au><au>Oliveira, Jaqueline C</au><au>Moreno, Daniel A</au><au>de Paula Queiroz, Rosane G</au><au>Scrideli, Carlos A</au><au>Tone, Luiz G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Zebularine induces chemosensitization to methotrexate and efficiently decreases AhR gene methylation in childhood acute lymphoblastic leukemia cells</atitle><jtitle>Anti-cancer drugs</jtitle><addtitle>Anticancer Drugs</addtitle><date>2014-01</date><risdate>2014</risdate><volume>25</volume><issue>1</issue><spage>72</spage><epage>81</epage><pages>72-81</pages><issn>0959-4973</issn><eissn>1473-5741</eissn><abstract>Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in childhood. Despite the advances in treatment, about 20% of patients relapse and/or die, indicating the need for different therapies for this group. Zebularine (ZB) is a potent DNA methyltransferase (DNMT) inhibitor and has been associated with gene demethylation and enhancement of tumor chemosensitivity. This study aimed to evaluate the effects of ZB, alone or combined with chemotherapeutics (methotrexate and vincristine), on childhood ALL cell lines. Cell proliferation, apoptosis, and clonogenic capacity were studied in Jurkat and ReH cell lines. Bisulfite modification, followed by methylation-specific PCR was carried out to evaluate aryl hydrocarbon receptor (AhR) methylation status. Gene expression of DNMT1, DNMT3a, DNMT3b, and AhR was assessed using qRT-PCR. Both cell cultures were sensitive to ZB, showing a dose-dependent and time-dependent response (P<0.05). ZB induced apoptosis and decreased clonogenic capacity in both cell lines. Combination with methotrexate resulted in a strong synergistic effect, whereas combination with vincristine led to an antagonistic response in both cell lines. ZB treatment decreased gene expression of the three DNMTs and induced AhR gene promoter demethylation and its re-expression. These results indicate that ZB may be a promising drug for the adjuvant treatment of ALL, mainly when combined with methotrexate.</abstract><cop>England</cop><pub>Wolters Kluwer Health | Lippincott Williams & Wilkins</pub><pmid>24052107</pmid><doi>10.1097/CAD.0000000000000028</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antineoplastic Agents - pharmacology Apoptosis - drug effects Basic Helix-Loop-Helix Transcription Factors - genetics Basic Helix-Loop-Helix Transcription Factors - metabolism Cell Line, Tumor Cytidine - analogs & derivatives Cytidine - pharmacology DNA Modification Methylases - antagonists & inhibitors Drug Antagonism Drug Resistance, Neoplasm Drug Synergism Humans Methotrexate - pharmacology Methylation Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism Receptors, Aryl Hydrocarbon - genetics Receptors, Aryl Hydrocarbon - metabolism Vincristine - pharmacology |
| title | Zebularine induces chemosensitization to methotrexate and efficiently decreases AhR gene methylation in childhood acute lymphoblastic leukemia cells |
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