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Epidermal growth factor receptor inhibitor gefitinib and valproic acid have been implicated in the treatment of malignancies including glioma involving autophagic and apoptotic mechanisms. Therefore, it is interesting to investigate whether a combination of gefitinib and valproic acid shows better cancer cell killing effect on human glioma cells. We found that a nontoxic concentration of valproic acid sensitized U87 and T98G glioma cells to gefitinib cytotoxicity by inhibiting cell growth and long\u2010term clonogenic survival. The augmented consequences were accompanied by the formation of autophagic vacuoles, conversion of microtubule\u2010associated protein\u20101 light chain 3\u2010II (LC3\u2010II), and degradation of p62. Autophagy inhibitor 3\u2010methyladenosine and chloroquine and genetic silencing of LC3 but not broad\u2010spectrum caspase inhibitor attenuated gefitinib\/valproic acid\u2010induced growth inhibition. Gefitinib\/valproic acid\u2010induced autophagy was accompanied by the activation of liver kinase\u2010B1 (LKB1)\/AMP\u2010activated protein kinase (AMPK)\/ULK1. Silencing of AMPK and ULK1 suppressed gefitinib\/valproic acid\u2010induced autophagy and growth inhibition. Mechanistic studies showed that gefitinib\/valproic acid increased intracellular reactive oxygen species generation and N\u2010acetyl cysteine attenuated gefitinib\/valproic acid\u2010caused autophagy and growth inhibition. In addition to demonstrating the autophagic mechanisms of gefitinib\/valproic acid, the results of this study further suggest that intracellular oxidative stress and the LKB1\/AMPK signaling might be a potential target for the development of therapeutic strategy against glioma. \u00a9 2015 IUBMB Life, 67(11):869\u2013879, 2015<\/jats:p>","DOI":"10.1002\/iub.1445","type":"journal-article","created":{"date-parts":[[2015,10,22]],"date-time":"2015-10-22T07:11:15Z","timestamp":1445497875000},"page":"869-879","source":"Crossref","is-referenced-by-count":30,"title":["Valproic acid sensitizes human glioma cells to gefitinib\u2010induced autophagy"],"prefix":"10.1002","volume":"67","author":[{"given":"Cheng\u2010Yi","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Surgery Feng Yuan Hospital  Taichung Taiwan"},{"name":"Graduate Institute of Pharmaceutical Science and Technology Central Taiwan University of Science and Technology  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian\u2010Ri","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Urology Taichung Veterans General Hospital  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chih\u2010Cheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Taichung Veterans General Hospital  Taichung Taiwan"},{"name":"Department of Financial and Computational Mathematics Providence University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yen\u2010Chuan","family":"Ou","sequence":"additional","affiliation":[{"name":"Division of Urology Taichung Veterans General Hospital  Taichung Taiwan"},{"name":"Department of Medical Research Taichung Veterans General Hospital  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen\u2010Ying","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine National Chung Hsing University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu\u2010Hsiang","family":"Kuan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Chung Shan Medical University  Taichung Taiwan"},{"name":"Department of Pharmacy Chung Shan Medical University Hospital  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen\u2010Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nursing HungKuang University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun\u2010Jung","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Research Taichung Veterans General Hospital  Taichung Taiwan"},{"name":"Department of Nursing HungKuang University  Taichung Taiwan"},{"name":"Institute of Biomedical Sciences National Chung Hsing University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,10,21]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2012.07781.x"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jocn.2004.04.001"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2011.07219.x"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.16.7727"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.7.2965"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.08.110"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-11-0606"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0044372"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2012.07731.x"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2002.01081.x"},{"key":"e_1_2_6_12_1","doi-asserted-by":"crossref","first-page":"3378","DOI":"10.2174\/138161207782360528","article-title":"Valproic acid as anti\u2010cancer drug","volume":"13","author":"Michaelis M.","year":"2007","journal-title":"Curr. 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