Valproic acid sensitizes human glioma cells to gefitinib‐induced autophagy. Issue 11 (21st October 2015)

• Record Type: Journal Article
• Authors: Chang, Cheng‐Yi; Li, Jian‐Ri; Wu, Chih‐Cheng; Ou, Yen‐Chuan; Chen, Wen‐Ying; Kuan, Yu‐Hsiang; Wang, Wen‐Yi; Chen, Chun‐Jung
• Is Part Of: IUBMB life. Volume 67:Issue 11(2015:Nov.)
• Page Start: 869
• Page End: 879
• Publication Date: 2015-10-21
• Subjects: autophagy -- EGFR -- gefitinib -- glioma -- valproic acid; Biochemistry -- Periodicals; Molecular biology -- Periodicals; 572.8
• DOI: 10.1002/iub.1445
• Languages: English
• ISSNs: 1521-6543

Abstract

Abstract: Autophagy and apoptosis represent important cellular processes involved in cancer cell killing mechanisms. 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‐term clonogenic survival. The augmented consequences were accompanied by the formation of autophagic vacuoles, conversion of microtubule‐associated protein‐1 light chain 3‐II (LC3‐II), and degradation of p62. Autophagy inhibitor 3‐methyladenosine and chloroquine and genetic silencing of LC3 but not broad‐spectrum caspase inhibitor attenuated gefitinib/valproic acid‐induced growth inhibition. Gefitinib/valproic acid‐induced autophagy was accompanied by the activation of liver kinase‐B1 (LKB1)/AMP‐activated protein kinase (AMPK)/ULK1. Silencing of AMPK and ULK1 suppressed gefitinib/valproic acid‐induced autophagy and growth inhibition. Mechanistic studies showed that gefitinib/valproic acid increased intracellular reactive oxygen species generation and N‐acetyl cysteine attenuated gefitinib/valproic acid‐caused 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. © 2015 IUBMB Life, 67(11):869–879, 2015