Valproic acid sensitizes human glioma cells to gefitinib‐induced autophagy

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.

Bisdemethoxycurcumin Enhances the Sensitivity of Non-small Cell Lung Cancer Cells to Icotinib via Dual Induction of Autophagy and Apoptosis

“…Also HDAC inhibition promote autophagy induction through multiple mechanisms including activation of oxidative stress [37], and oxidative stress is considered as activating force for autophagy induction [25]. Thus, the combination of icotinib and BDMC might create oxidative stress-related microenvironments favorable for autophagy and elevated oxidative burden drives autophagy moving forward [38]. Interestingly, apoptosis reaction by the two drugs combination was attenuated by CQ, 3-MA and NAC, or knockdown of Beclin-1, signifying that icotinib plus BDMC induced autophagy-related apoptosis and this effect is associated with oxidative stress.…”

“…DNA damage can activate autophagy through various DNA damage responses signaling at multiple levels. Also, autophagy is directly involved in DNA damage repair [38,40].…”

Ischemic preconditioning improved renal ischemia/reperfusion injury and hyperglycemia

“…Data of Western blotting revealed a promoting effect that IPC has in the induction of autophagy after renal I/R, together with an increased Atg12 expression and AMPK phosphorylation. AMPK favors an autophagy complex assembly through a phosphorylation mechanism (18). Relevant studies also show a renoprotective effect that AMPK activator has against renal I/R injury and the Nrf2 inducing effect of AMPK (28).…”

“…Autophagy displays dual roles in the regulation of cell death and also represents an alternative way to inhibit renal I/R-induced apoptosis (11). The expression and activation of several biochemical molecules due to autophagy, such as LC3, Atg12, and AMPK, were determined (18,19). An increased LC3 II conversion was detected in the kidneys of renal I/R rats (Fig.…”

Endoplasmic Reticulum Stress Contributes to Indomethacin-Induced Glioma Apoptosis

“…Human U87 MG glioblastoma (ATCC HTB-14) and H4 neuroglioma (ATCC HTB-148) cells were cultured in Dulbecco's modified Eagle medium (DMEM) containing 10% fetal bovine serum (FBS) [51].…”