The Critical Role of Redox Homeostasis in Shikonin-Induced HL-60 Cell Differentiation via Unique Modulation of the Nrf2/ARE Pathway
Among various cancer cell lines, the leukemia cell line HL-60 was most sensitive to Shikonin, with evidence showing both the prooxidative activities and proapoptotic effects of micromolar concentrations of Shikonin. However, the mechanism involved in the cytotoxicity of Shikonin in the submicromolar...
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| Veröffentlicht in: | Oxidative medicine and cellular longevity 2012-01, Vol.2012 (2012), p.1-12 |
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| creator | Zhang, Bo Chen, Na Chen, Hongmei Wang, Zhenhua Zheng, Qiusheng |
| description | Among various cancer cell lines, the leukemia cell line HL-60 was most sensitive to Shikonin, with evidence showing both the prooxidative activities and proapoptotic effects of micromolar concentrations of Shikonin. However, the mechanism involved in the cytotoxicity of Shikonin in the submicromolar range has not been fully characterized. Using biochemical and free radical biological experiments in vitro, we identified the prodifferentiated profiles of Shikonin and evaluated the redox homeostasis during HL-60 differentiation. The data showed a strong dose-response relationship between Shikonin exposure and the characteristics of HL-60 differentiation in terms of morphology changes, nitroblue tetrazolium (NBT) reductive activity, and the expression level of surface antigens CD11b/CD14. During drug exposure, intercellular redox homeostasis changes towards oxidation are necessary to support Shikonin-induced differentiation, which was proven by additional enzymatic and non-enzymatic redox modulators. A statistically significant and dose-dependent increase (P |
| doi_str_mv | 10.1155/2012/781516 |
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However, the mechanism involved in the cytotoxicity of Shikonin in the submicromolar range has not been fully characterized. Using biochemical and free radical biological experiments in vitro, we identified the prodifferentiated profiles of Shikonin and evaluated the redox homeostasis during HL-60 differentiation. The data showed a strong dose-response relationship between Shikonin exposure and the characteristics of HL-60 differentiation in terms of morphology changes, nitroblue tetrazolium (NBT) reductive activity, and the expression level of surface antigens CD11b/CD14. During drug exposure, intercellular redox homeostasis changes towards oxidation are necessary to support Shikonin-induced differentiation, which was proven by additional enzymatic and non-enzymatic redox modulators. A statistically significant and dose-dependent increase (P<0.05) was recorded with regard to the unique expression levels of the Nrf2/ARE downstream target genes in HL-60 cells undergoing late differentiation, which were restored with further antioxidants employed with the Shikonin treatment. Our research demonstrated that Shikonin is a differentiation-inducing agent, and its mechanisms involve the Nrf2/ARE pathway to modulate the intercellular redox homeostasis, thus facilitating differentiation.</description><identifier>ISSN: 1942-0900</identifier><identifier>EISSN: 1942-0994</identifier><identifier>DOI: 10.1155/2012/781516</identifier><identifier>PMID: 23119122</identifier><language>eng</language><publisher>Cairo, Egypt: Hindawi Puplishing Corporation</publisher><subject>Antioxidants - metabolism ; CD11b Antigen - genetics ; CD11b Antigen - metabolism ; Cell Differentiation - drug effects ; Cell Proliferation - drug effects ; Cell Shape - drug effects ; Extracellular Space - drug effects ; Extracellular Space - metabolism ; HL-60 Cells ; Homeostasis - drug effects ; Humans ; Lipopolysaccharide Receptors - genetics ; Lipopolysaccharide Receptors - metabolism ; Models, Biological ; Naphthoquinones - pharmacology ; NF-E2-Related Factor 2 - metabolism ; Nitroblue Tetrazolium - metabolism ; Oxidation-Reduction - drug effects ; Response Elements - genetics ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Signal Transduction - drug effects</subject><ispartof>Oxidative medicine and cellular longevity, 2012-01, Vol.2012 (2012), p.1-12</ispartof><rights>Copyright © 2012 Bo Zhang et al.</rights><rights>Copyright © 2012 Bo Zhang et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c504t-ac64edbfa47e947617c5cca33d15132ce5110da6cd413ce40e65cdc64fbfa9d93</citedby><cites>FETCH-LOGICAL-c504t-ac64edbfa47e947617c5cca33d15132ce5110da6cd413ce40e65cdc64fbfa9d93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478756/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478756/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23119122$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Rameshwar, Pranela</contributor><creatorcontrib>Zhang, Bo</creatorcontrib><creatorcontrib>Chen, Na</creatorcontrib><creatorcontrib>Chen, Hongmei</creatorcontrib><creatorcontrib>Wang, Zhenhua</creatorcontrib><creatorcontrib>Zheng, Qiusheng</creatorcontrib><title>The Critical Role of Redox Homeostasis in Shikonin-Induced HL-60 Cell Differentiation via Unique Modulation of the Nrf2/ARE Pathway</title><title>Oxidative medicine and cellular longevity</title><addtitle>Oxid Med Cell Longev</addtitle><description>Among various cancer cell lines, the leukemia cell line HL-60 was most sensitive to Shikonin, with evidence showing both the prooxidative activities and proapoptotic effects of micromolar concentrations of Shikonin. However, the mechanism involved in the cytotoxicity of Shikonin in the submicromolar range has not been fully characterized. Using biochemical and free radical biological experiments in vitro, we identified the prodifferentiated profiles of Shikonin and evaluated the redox homeostasis during HL-60 differentiation. The data showed a strong dose-response relationship between Shikonin exposure and the characteristics of HL-60 differentiation in terms of morphology changes, nitroblue tetrazolium (NBT) reductive activity, and the expression level of surface antigens CD11b/CD14. During drug exposure, intercellular redox homeostasis changes towards oxidation are necessary to support Shikonin-induced differentiation, which was proven by additional enzymatic and non-enzymatic redox modulators. A statistically significant and dose-dependent increase (P<0.05) was recorded with regard to the unique expression levels of the Nrf2/ARE downstream target genes in HL-60 cells undergoing late differentiation, which were restored with further antioxidants employed with the Shikonin treatment. Our research demonstrated that Shikonin is a differentiation-inducing agent, and its mechanisms involve the Nrf2/ARE pathway to modulate the intercellular redox homeostasis, thus facilitating differentiation.</description><subject>Antioxidants - metabolism</subject><subject>CD11b Antigen - genetics</subject><subject>CD11b Antigen - metabolism</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Shape - drug effects</subject><subject>Extracellular Space - drug effects</subject><subject>Extracellular Space - metabolism</subject><subject>HL-60 Cells</subject><subject>Homeostasis - drug effects</subject><subject>Humans</subject><subject>Lipopolysaccharide Receptors - genetics</subject><subject>Lipopolysaccharide Receptors - metabolism</subject><subject>Models, Biological</subject><subject>Naphthoquinones - pharmacology</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Nitroblue Tetrazolium - metabolism</subject><subject>Oxidation-Reduction - drug effects</subject><subject>Response Elements - genetics</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Signal Transduction - drug effects</subject><issn>1942-0900</issn><issn>1942-0994</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>RHX</sourceid><sourceid>EIF</sourceid><recordid>eNqFkc1v1DAQxS0EoqVw4gzyEYHCehzb2VyQqqWwlZYPLe3Zcu0xMWTtEictPfOP4yplBSdOtjy_eTPPj5CnwF4DSLngDPiiWYIEdY8cQit4xdpW3N_fGTsgj3L-xpiquYCH5IDXAC1wfkh-nXVIV0MYgzU93aYeafJ0iy79pOu0w5RHk0OmIdIvXfieYojVaXSTRUfXm0oxusK-p2-D9zhgHIMZQ4r0Khh6HsOPCemH5KZ-fi3KYxn3cfB8cbw9oZ_N2F2bm8fkgTd9xid35xE5f3dytlpXm0_vT1fHm8pKJsbKWCXQXXgjGmxFo6Cx0lpT165Yr7lFCcCcUdYJqC0KhkpaV5p86WldWx-RN7Pu5XSxQ2fLuoPp9eUQdma40ckE_W8lhk5_TVe6Fs2ykaoIvLgTGFKxlke9C9kW_yZimrIG4EqBknxZ0FczaoeU84B-PwaYvo1N38am59gK_fzvzfbsn5wK8HIGuhCduQ7_UXs2w1gQ9GYPi7YpP1X_Bqzfqns</recordid><startdate>20120101</startdate><enddate>20120101</enddate><creator>Zhang, Bo</creator><creator>Chen, Na</creator><creator>Chen, Hongmei</creator><creator>Wang, Zhenhua</creator><creator>Zheng, Qiusheng</creator><general>Hindawi Puplishing Corporation</general><general>Hindawi Publishing Corporation</general><scope>ADJCN</scope><scope>AHFXO</scope><scope>RHU</scope><scope>RHW</scope><scope>RHX</scope><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>5PM</scope></search><sort><creationdate>20120101</creationdate><title>The Critical Role of Redox Homeostasis in Shikonin-Induced HL-60 Cell Differentiation via Unique Modulation of the Nrf2/ARE Pathway</title><author>Zhang, Bo ; Chen, Na ; Chen, Hongmei ; Wang, Zhenhua ; Zheng, Qiusheng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c504t-ac64edbfa47e947617c5cca33d15132ce5110da6cd413ce40e65cdc64fbfa9d93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Antioxidants - metabolism</topic><topic>CD11b Antigen - genetics</topic><topic>CD11b Antigen - metabolism</topic><topic>Cell Differentiation - drug effects</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Shape - drug effects</topic><topic>Extracellular Space - drug effects</topic><topic>Extracellular Space - metabolism</topic><topic>HL-60 Cells</topic><topic>Homeostasis - drug effects</topic><topic>Humans</topic><topic>Lipopolysaccharide Receptors - genetics</topic><topic>Lipopolysaccharide Receptors - metabolism</topic><topic>Models, Biological</topic><topic>Naphthoquinones - pharmacology</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>Nitroblue Tetrazolium - metabolism</topic><topic>Oxidation-Reduction - drug effects</topic><topic>Response Elements - genetics</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Signal Transduction - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Bo</creatorcontrib><creatorcontrib>Chen, Na</creatorcontrib><creatorcontrib>Chen, Hongmei</creatorcontrib><creatorcontrib>Wang, Zhenhua</creatorcontrib><creatorcontrib>Zheng, Qiusheng</creatorcontrib><collection>الدوريات العلمية والإحصائية - e-Marefa Academic and Statistical Periodicals</collection><collection>معرفة - المحتوى العربي الأكاديمي المتكامل - e-Marefa Academic Complete</collection><collection>Hindawi Publishing Complete</collection><collection>Hindawi Publishing Subscription Journals</collection><collection>Hindawi Publishing Open Access Journals</collection><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>PubMed Central (Full Participant titles)</collection><jtitle>Oxidative medicine and cellular longevity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Bo</au><au>Chen, Na</au><au>Chen, Hongmei</au><au>Wang, Zhenhua</au><au>Zheng, Qiusheng</au><au>Rameshwar, Pranela</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Critical Role of Redox Homeostasis in Shikonin-Induced HL-60 Cell Differentiation via Unique Modulation of the Nrf2/ARE Pathway</atitle><jtitle>Oxidative medicine and cellular longevity</jtitle><addtitle>Oxid Med Cell Longev</addtitle><date>2012-01-01</date><risdate>2012</risdate><volume>2012</volume><issue>2012</issue><spage>1</spage><epage>12</epage><pages>1-12</pages><issn>1942-0900</issn><eissn>1942-0994</eissn><abstract>Among various cancer cell lines, the leukemia cell line HL-60 was most sensitive to Shikonin, with evidence showing both the prooxidative activities and proapoptotic effects of micromolar concentrations of Shikonin. However, the mechanism involved in the cytotoxicity of Shikonin in the submicromolar range has not been fully characterized. Using biochemical and free radical biological experiments in vitro, we identified the prodifferentiated profiles of Shikonin and evaluated the redox homeostasis during HL-60 differentiation. The data showed a strong dose-response relationship between Shikonin exposure and the characteristics of HL-60 differentiation in terms of morphology changes, nitroblue tetrazolium (NBT) reductive activity, and the expression level of surface antigens CD11b/CD14. During drug exposure, intercellular redox homeostasis changes towards oxidation are necessary to support Shikonin-induced differentiation, which was proven by additional enzymatic and non-enzymatic redox modulators. A statistically significant and dose-dependent increase (P<0.05) was recorded with regard to the unique expression levels of the Nrf2/ARE downstream target genes in HL-60 cells undergoing late differentiation, which were restored with further antioxidants employed with the Shikonin treatment. Our research demonstrated that Shikonin is a differentiation-inducing agent, and its mechanisms involve the Nrf2/ARE pathway to modulate the intercellular redox homeostasis, thus facilitating differentiation.</abstract><cop>Cairo, Egypt</cop><pub>Hindawi Puplishing Corporation</pub><pmid>23119122</pmid><doi>10.1155/2012/781516</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; Wiley Online Library Open Access; PubMed Central; Alma/SFX Local Collection |
| subjects | Antioxidants - metabolism CD11b Antigen - genetics CD11b Antigen - metabolism Cell Differentiation - drug effects Cell Proliferation - drug effects Cell Shape - drug effects Extracellular Space - drug effects Extracellular Space - metabolism HL-60 Cells Homeostasis - drug effects Humans Lipopolysaccharide Receptors - genetics Lipopolysaccharide Receptors - metabolism Models, Biological Naphthoquinones - pharmacology NF-E2-Related Factor 2 - metabolism Nitroblue Tetrazolium - metabolism Oxidation-Reduction - drug effects Response Elements - genetics RNA, Messenger - genetics RNA, Messenger - metabolism Signal Transduction - drug effects |
| title | The Critical Role of Redox Homeostasis in Shikonin-Induced HL-60 Cell Differentiation via Unique Modulation of the Nrf2/ARE Pathway |
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