Kotomolide A arrests cell cycle progression and induces apoptosis through the induction of ATM/p53 and the initiation of mitochondrial system in human non-small cell lung cancer A549 cells
This study first investigates the anticancer effect of kotomolide A (KTA) in human non-small cell lung cancer cells, A549. KTA has exhibited effective cell growth inhibition by inducing cancer cells to undergo G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased the...
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| Veröffentlicht in: | Food and chemical toxicology 2008-07, Vol.46 (7), p.2476-2484 |
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| creator | Chen, Chung-Yi Hsu, Ya-Ling Tsai, Yu-Chieh Kuo, Po-Lin |
| description | This study first investigates the anticancer effect of kotomolide A (KTA) in human non-small cell lung cancer cells, A549. KTA has exhibited effective cell growth inhibition by inducing cancer cells to undergo G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased the activation of ataxia telangiectasia-mutated (ATM). Activation of ATM by KTA phosphorylated p53 at Serine15, resulting in increased stability of p53 by decreasing p53 and murine double minute-2 (MDM2) interaction. In addition, KTA-mediated G2/M phase arrest also was associated with the decrease in the amounts of cyclinB1, cyclinA, Cdc2 and Cdc25C and increase in the phosphorylation of Chk2, Cdc25C and Cdc2. Specific ATM inhibitor, caffeine, significantly decreased KTA-mediated G2/M arrest by inhibiting the phosphorylation of p53 (Serine15) and Chk2. KTA treatment triggered the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in mitochondrial membrane potential loss and caspase-9 activation. Taken together, these results suggest a critical role for ATM and p53 in KTA-induced G2/M arrest and apoptosis of human non-small cell lung cancer cells. |
| doi_str_mv | 10.1016/j.fct.2008.04.016 |
| format | Article |
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KTA has exhibited effective cell growth inhibition by inducing cancer cells to undergo G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased the activation of ataxia telangiectasia-mutated (ATM). Activation of ATM by KTA phosphorylated p53 at Serine15, resulting in increased stability of p53 by decreasing p53 and murine double minute-2 (MDM2) interaction. In addition, KTA-mediated G2/M phase arrest also was associated with the decrease in the amounts of cyclinB1, cyclinA, Cdc2 and Cdc25C and increase in the phosphorylation of Chk2, Cdc25C and Cdc2. Specific ATM inhibitor, caffeine, significantly decreased KTA-mediated G2/M arrest by inhibiting the phosphorylation of p53 (Serine15) and Chk2. KTA treatment triggered the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in mitochondrial membrane potential loss and caspase-9 activation. Taken together, these results suggest a critical role for ATM and p53 in KTA-induced G2/M arrest and apoptosis of human non-small cell lung cancer cells.</description><identifier>ISSN: 0278-6915</identifier><identifier>EISSN: 1873-6351</identifier><identifier>DOI: 10.1016/j.fct.2008.04.016</identifier><identifier>PMID: 18511169</identifier><identifier>CODEN: FCTOD7</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>4-Butyrolactone - analogs & derivatives ; 4-Butyrolactone - pharmacology ; Animals ; anticarcinogenic activity ; Antineoplastic Agents, Phytogenic - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Ataxia Telangiectasia Mutated Proteins ; ataxia telangiectasia-mutated ; ATM ; Biological and medical sciences ; biological resistance ; Caspase 9 - metabolism ; caspase-9 ; CDC2 Protein Kinase ; cdc25 Phosphatases - metabolism ; Cell cycle ; Cell Cycle - drug effects ; Cell Cycle Proteins - metabolism ; cell growth ; cell lines ; Cinnamomum ; Cinnamomum kotoense ; Cyclin A - metabolism ; Cyclin B - metabolism ; Cyclin B1 ; Cyclin-Dependent Kinases ; DNA-Binding Proteins - metabolism ; Dose-Response Relationship, Drug ; enzyme activation ; human diseases ; Humans ; inhibitors ; Kotomolide A ; leaves ; lung neoplasms ; Medical sciences ; Mice ; mitochondria ; Mitochondria - drug effects ; Mitochondria - physiology ; Mitochondrial pathway ; murine double minute-2 ; p53 ; Phosphorylation ; plant extracts ; Pneumology ; protein kinases ; Protein-Serine-Threonine Kinases - metabolism ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; signal transduction ; Toxicology ; transcription factors ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53 - metabolism ; Tumor Suppressor Proteins - metabolism ; Tumors of the respiratory system and mediastinum</subject><ispartof>Food and chemical toxicology, 2008-07, Vol.46 (7), p.2476-2484</ispartof><rights>2008</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c436t-109e10768ed2b170ed36bca8eafedccf86facf9df78ddc432cbaae7de49c4b353</citedby><cites>FETCH-LOGICAL-c436t-109e10768ed2b170ed36bca8eafedccf86facf9df78ddc432cbaae7de49c4b353</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0278691508001750$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20444280$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18511169$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Chung-Yi</creatorcontrib><creatorcontrib>Hsu, Ya-Ling</creatorcontrib><creatorcontrib>Tsai, Yu-Chieh</creatorcontrib><creatorcontrib>Kuo, Po-Lin</creatorcontrib><title>Kotomolide A arrests cell cycle progression and induces apoptosis through the induction of ATM/p53 and the initiation of mitochondrial system in human non-small cell lung cancer A549 cells</title><title>Food and chemical toxicology</title><addtitle>Food Chem Toxicol</addtitle><description>This study first investigates the anticancer effect of kotomolide A (KTA) in human non-small cell lung cancer cells, A549. KTA has exhibited effective cell growth inhibition by inducing cancer cells to undergo G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased the activation of ataxia telangiectasia-mutated (ATM). Activation of ATM by KTA phosphorylated p53 at Serine15, resulting in increased stability of p53 by decreasing p53 and murine double minute-2 (MDM2) interaction. In addition, KTA-mediated G2/M phase arrest also was associated with the decrease in the amounts of cyclinB1, cyclinA, Cdc2 and Cdc25C and increase in the phosphorylation of Chk2, Cdc25C and Cdc2. Specific ATM inhibitor, caffeine, significantly decreased KTA-mediated G2/M arrest by inhibiting the phosphorylation of p53 (Serine15) and Chk2. KTA treatment triggered the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in mitochondrial membrane potential loss and caspase-9 activation. Taken together, these results suggest a critical role for ATM and p53 in KTA-induced G2/M arrest and apoptosis of human non-small cell lung cancer cells.</description><subject>4-Butyrolactone - analogs & derivatives</subject><subject>4-Butyrolactone - pharmacology</subject><subject>Animals</subject><subject>anticarcinogenic activity</subject><subject>Antineoplastic Agents, Phytogenic - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Ataxia Telangiectasia Mutated Proteins</subject><subject>ataxia telangiectasia-mutated</subject><subject>ATM</subject><subject>Biological and medical sciences</subject><subject>biological resistance</subject><subject>Caspase 9 - metabolism</subject><subject>caspase-9</subject><subject>CDC2 Protein Kinase</subject><subject>cdc25 Phosphatases - metabolism</subject><subject>Cell cycle</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>cell growth</subject><subject>cell lines</subject><subject>Cinnamomum</subject><subject>Cinnamomum kotoense</subject><subject>Cyclin A - metabolism</subject><subject>Cyclin B - metabolism</subject><subject>Cyclin B1</subject><subject>Cyclin-Dependent Kinases</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>enzyme activation</subject><subject>human diseases</subject><subject>Humans</subject><subject>inhibitors</subject><subject>Kotomolide A</subject><subject>leaves</subject><subject>lung neoplasms</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>mitochondria</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - physiology</subject><subject>Mitochondrial pathway</subject><subject>murine double minute-2</subject><subject>p53</subject><subject>Phosphorylation</subject><subject>plant extracts</subject><subject>Pneumology</subject><subject>protein kinases</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>signal transduction</subject><subject>Toxicology</subject><subject>transcription factors</subject><subject>Tumor Cells, Cultured</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumor Suppressor Proteins - metabolism</subject><subject>Tumors of the respiratory system and mediastinum</subject><issn>0278-6915</issn><issn>1873-6351</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc2O1DAQhCMEYoeFB-ACvsAt2bbj_InTaMWfWMSB3bPl2O0ZjxJ7sJOV5t14OJzNADc4tdT9VatUlWUvKRQUaH11KIyaCgbQFsCLtHmUbWjblHldVvRxtgHWtHnd0eoiexbjAQAa2tRPswvaVpTSuttkP7_4yY9-sBrJlsgQME6RKBwGok5qQHIMfpeW0XpHpNPEOj0rjEQe_XHy0UYy7YOfd_s0cb1OC-sN2d5-vTpW5YNsPdrJyt_X0U5e7b3TwcqBxFOccEwI2c-jdMR5l8dRLjYWL8PsdkRJpzCQbcW7h218nj0xcoj44jwvs7sP72-vP-U33z5-vt7e5IqX9ZRT6JBCU7eoWU8bQF3WvZItSoNaKdPWRirTadO0WicJU72U2GjkneJ9WZWX2dv1bwrjx5wSEqONiwPp0M9RNLSuWqDdf0HaVSVwxhNIV1AFH2NAI47BjjKcBAWxdCsOInUrlm4FcJE2SfPq_HzuR9R_FecyE_DmDMio5GBCysvGPxwDzjlrIXGvV85IL-QuJObuOwNaAnSsAbZ8ercSmFK9txhEVBZT-toGTLa0t_8w-gslmM9S</recordid><startdate>20080701</startdate><enddate>20080701</enddate><creator>Chen, Chung-Yi</creator><creator>Hsu, Ya-Ling</creator><creator>Tsai, Yu-Chieh</creator><creator>Kuo, Po-Lin</creator><general>Elsevier Ltd</general><general>Elsevier Science</general><scope>FBQ</scope><scope>IQODW</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>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20080701</creationdate><title>Kotomolide A arrests cell cycle progression and induces apoptosis through the induction of ATM/p53 and the initiation of mitochondrial system in human non-small cell lung cancer A549 cells</title><author>Chen, Chung-Yi ; Hsu, Ya-Ling ; Tsai, Yu-Chieh ; Kuo, Po-Lin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c436t-109e10768ed2b170ed36bca8eafedccf86facf9df78ddc432cbaae7de49c4b353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>4-Butyrolactone - analogs & derivatives</topic><topic>4-Butyrolactone - pharmacology</topic><topic>Animals</topic><topic>anticarcinogenic activity</topic><topic>Antineoplastic Agents, Phytogenic - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Ataxia Telangiectasia Mutated Proteins</topic><topic>ataxia telangiectasia-mutated</topic><topic>ATM</topic><topic>Biological and medical sciences</topic><topic>biological resistance</topic><topic>Caspase 9 - metabolism</topic><topic>caspase-9</topic><topic>CDC2 Protein Kinase</topic><topic>cdc25 Phosphatases - metabolism</topic><topic>Cell cycle</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>cell growth</topic><topic>cell lines</topic><topic>Cinnamomum</topic><topic>Cinnamomum kotoense</topic><topic>Cyclin A - metabolism</topic><topic>Cyclin B - metabolism</topic><topic>Cyclin B1</topic><topic>Cyclin-Dependent Kinases</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>enzyme activation</topic><topic>human diseases</topic><topic>Humans</topic><topic>inhibitors</topic><topic>Kotomolide A</topic><topic>leaves</topic><topic>lung neoplasms</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>mitochondria</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - physiology</topic><topic>Mitochondrial pathway</topic><topic>murine double minute-2</topic><topic>p53</topic><topic>Phosphorylation</topic><topic>plant extracts</topic><topic>Pneumology</topic><topic>protein kinases</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Proto-Oncogene Proteins c-bcl-2 - metabolism</topic><topic>signal transduction</topic><topic>Toxicology</topic><topic>transcription factors</topic><topic>Tumor Cells, Cultured</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumor Suppressor Proteins - metabolism</topic><topic>Tumors of the respiratory system and mediastinum</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Chung-Yi</creatorcontrib><creatorcontrib>Hsu, Ya-Ling</creatorcontrib><creatorcontrib>Tsai, Yu-Chieh</creatorcontrib><creatorcontrib>Kuo, Po-Lin</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Food and chemical toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Chung-Yi</au><au>Hsu, Ya-Ling</au><au>Tsai, Yu-Chieh</au><au>Kuo, Po-Lin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Kotomolide A arrests cell cycle progression and induces apoptosis through the induction of ATM/p53 and the initiation of mitochondrial system in human non-small cell lung cancer A549 cells</atitle><jtitle>Food and chemical toxicology</jtitle><addtitle>Food Chem Toxicol</addtitle><date>2008-07-01</date><risdate>2008</risdate><volume>46</volume><issue>7</issue><spage>2476</spage><epage>2484</epage><pages>2476-2484</pages><issn>0278-6915</issn><eissn>1873-6351</eissn><coden>FCTOD7</coden><abstract>This study first investigates the anticancer effect of kotomolide A (KTA) in human non-small cell lung cancer cells, A549. KTA has exhibited effective cell growth inhibition by inducing cancer cells to undergo G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased the activation of ataxia telangiectasia-mutated (ATM). Activation of ATM by KTA phosphorylated p53 at Serine15, resulting in increased stability of p53 by decreasing p53 and murine double minute-2 (MDM2) interaction. In addition, KTA-mediated G2/M phase arrest also was associated with the decrease in the amounts of cyclinB1, cyclinA, Cdc2 and Cdc25C and increase in the phosphorylation of Chk2, Cdc25C and Cdc2. Specific ATM inhibitor, caffeine, significantly decreased KTA-mediated G2/M arrest by inhibiting the phosphorylation of p53 (Serine15) and Chk2. KTA treatment triggered the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in mitochondrial membrane potential loss and caspase-9 activation. Taken together, these results suggest a critical role for ATM and p53 in KTA-induced G2/M arrest and apoptosis of human non-small cell lung cancer cells.</abstract><cop>Oxford</cop><cop>New York, NY</cop><pub>Elsevier Ltd</pub><pmid>18511169</pmid><doi>10.1016/j.fct.2008.04.016</doi><tpages>9</tpages></addata></record> |
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| ispartof | Food and chemical toxicology, 2008-07, Vol.46 (7), p.2476-2484 |
| issn | 0278-6915 1873-6351 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | 4-Butyrolactone - analogs & derivatives 4-Butyrolactone - pharmacology Animals anticarcinogenic activity Antineoplastic Agents, Phytogenic - pharmacology Apoptosis Apoptosis - drug effects Ataxia Telangiectasia Mutated Proteins ataxia telangiectasia-mutated ATM Biological and medical sciences biological resistance Caspase 9 - metabolism caspase-9 CDC2 Protein Kinase cdc25 Phosphatases - metabolism Cell cycle Cell Cycle - drug effects Cell Cycle Proteins - metabolism cell growth cell lines Cinnamomum Cinnamomum kotoense Cyclin A - metabolism Cyclin B - metabolism Cyclin B1 Cyclin-Dependent Kinases DNA-Binding Proteins - metabolism Dose-Response Relationship, Drug enzyme activation human diseases Humans inhibitors Kotomolide A leaves lung neoplasms Medical sciences Mice mitochondria Mitochondria - drug effects Mitochondria - physiology Mitochondrial pathway murine double minute-2 p53 Phosphorylation plant extracts Pneumology protein kinases Protein-Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins c-bcl-2 - metabolism signal transduction Toxicology transcription factors Tumor Cells, Cultured Tumor Suppressor Protein p53 - metabolism Tumor Suppressor Proteins - metabolism Tumors of the respiratory system and mediastinum |
| title | Kotomolide A arrests cell cycle progression and induces apoptosis through the induction of ATM/p53 and the initiation of mitochondrial system in human non-small cell lung cancer A549 cells |
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