{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T15:59:51Z","timestamp":1791993591754,"version":"4.4.0"},"reference-count":60,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2017,4,27]],"date-time":"2017-04-27T00:00:00Z","timestamp":1493251200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81502582"],"award-info":[{"award-number":["81502582"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U1603125"],"award-info":[{"award-number":["U1603125"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["FEBS Open Bio"],"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:p>Effective drug combinations have the potential to strengthen therapeutic efficacy and combat drug resistance. Both melatonin and valproic acid (<jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>) exhibit antitumor activities in various cancer cells. The aim of this study was to evaluate the cell death pathways initiated by anticancer combinatorial effects of melatonin and <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> in bladder cancer cells. The results demonstrated that the combination of melatonin and <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> leads to significant synergistic growth inhibition of <jats:styled-content style=\"fixed-case\">UC<\/jats:styled-content>3 bladder cancer cells. Gene expression studies revealed that cotreatment with melatonin and <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> triggered the up\u2010regulation of certain genes related to apoptosis (<jats:styled-content style=\"fixed-case\">TNFRSF<\/jats:styled-content>10A and <jats:styled-content style=\"fixed-case\">TNFRSF<\/jats:styled-content>10B), autophagy (<jats:styled-content style=\"fixed-case\">BECN<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> ATG<\/jats:styled-content>3 and <jats:styled-content style=\"fixed-case\">ATG<\/jats:styled-content>5) and necrosis (<jats:styled-content style=\"fixed-case\">MLKL<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> PARP<\/jats:styled-content>\u20101 and <jats:styled-content style=\"fixed-case\">RIPK<\/jats:styled-content>1). The combinatorial treatment increased the expression of endoplasmic reticulum (<jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>)\u2010stress\u2010related genes <jats:styled-content style=\"fixed-case\">ATF<\/jats:styled-content>6, <jats:styled-content style=\"fixed-case\">IRE<\/jats:styled-content>1, <jats:styled-content style=\"fixed-case\">EDEM<\/jats:styled-content>1 and <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>dj4. Cotreatment with melatonin and <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> enhanced the expression of E\u2010cadherin, and decreased the expression of <jats:italic>N<\/jats:italic>\u2010cadherin, Fibronectin, Snail and Slug. Furthermore, the Wnt pathway and Raf\/<jats:styled-content style=\"fixed-case\">MEK<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content> pathway were activated by combinatorial treatment. However, the effects on the expression of certain genes were not further enhanced in cells following combinatorial treatment in comparison to individual treatment of melatonin or <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content>. In summary, these findings provided evidence that cotreatment with melatonin and <jats:styled-content style=\"fixed-case\">VPA<\/jats:styled-content> exerted increased cytotoxicity by regulating cell death pathways in <jats:styled-content style=\"fixed-case\">UC<\/jats:styled-content>3 bladder cancer cells, but the clinical significance of combinatorial treatment still needs to be further exploited.<\/jats:p>","DOI":"10.1002\/2211-5463.12223","type":"journal-article","created":{"date-parts":[[2017,4,5]],"date-time":"2017-04-05T18:48:29Z","timestamp":1491418109000},"page":"798-810","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Evaluation of cell death pathways initiated by antitumor drugs melatonin and valproic acid in bladder cancer cells"],"prefix":"10.1002","volume":"7","author":[{"given":"Siwei","family":"Liu","sequence":"first","affiliation":[{"name":"College of Life and Health Sciences Northeastern University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bilin","family":"Liang","sequence":"additional","affiliation":[{"name":"College of Life and Health Sciences Northeastern University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiting","family":"Jia","sequence":"additional","affiliation":[{"name":"College of Life and Health Sciences Northeastern University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Jiao","sequence":"additional","affiliation":[{"name":"College of Life and Health Sciences Northeastern University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongqiu","family":"Pang","sequence":"additional","affiliation":[{"name":"College of Life and Health Sciences Northeastern University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongye","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Life and Health Sciences Northeastern University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,4,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrurol.2015.231"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-8722-4-17"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1385\/CBB:34:2:237"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-16-0158"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.7314\/APJCP.2015.16.14.5835"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10103-016-2016-6"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2014.09.033"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1159\/000366305"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-079X.2010.00812.x"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12092"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12308"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0150407"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8009"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2015.01.003"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2014.11.001"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12226"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2015.10.012"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-079X.2008.00587.x"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12261"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/CAD.0b013e32834a2c70"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2013.1565"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2015.3213"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-009-5156-9"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.24.6969"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.2012.694425"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2009.08795.x"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.105"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/8290562"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.01610"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M408678200"},{"key":"e_1_2_8_32_1","first-page":"1","article-title":"Curcumin protects neuronal cells against status epilepticus\u2010induced hippocampal damage through induction of autophagy and inhibition of necroptosis","volume":"9","author":"Wang J","year":"2016","journal-title":"Can J Physiol Pharmacol"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-59745-157-4_4"},{"key":"e_1_2_8_34_1","first-page":"1","article-title":"Autophagy is a regulator of TRAIL\u2010induced apoptosis in NSCLC A549 cells","volume":"18","author":"Chen Y","year":"2017","journal-title":"J Cell Commun Signal"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2013.171"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13608"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0606526103"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12264"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.15150"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12295"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2016.10.034"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2015.10.008"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1159\/000453164"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17040526"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12333"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2016.12.017"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2016.4880"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/502676"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2016.120"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-0278"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.423"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2016.5950"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2016.3712"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2016.10.023"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12182"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2016.06.004"},{"key":"e_1_2_8_57_1","first-page":"578","article-title":"Wnt signaling pathway participates in valproic acid\u2010induced neuronal differentiation of neural stem cells","volume":"8","author":"Wang L","year":"2015","journal-title":"Int J Clin Exp Pathol"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1292\/jvms.70.1219"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.5507\/bp.2012.038"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12142"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1080\/15384047.2016.1276132"}],"container-title":["FEBS Open Bio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2F2211-5463.12223","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/2211-5463.12223","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T07:06:30Z","timestamp":1696575990000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1002\/2211-5463.12223"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,27]]},"references-count":60,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2017,6]]}},"alternative-id":["10.1002\/2211-5463.12223"],"URL":"https:\/\/doi.org\/10.1002\/2211-5463.12223","archive":["Portico"],"relation":{},"ISSN":["2211-5463","2211-5463"],"issn-type":[{"value":"2211-5463","type":"print"},{"value":"2211-5463","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,27]]},"assertion":[{"value":"2017-03-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-03-24","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-04-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}