Inhibition of Mitochondria- and Endoplasmic Reticulum Stress-Mediated Autophagy Augments Temozolomide-Induced Apoptosis in Glioma Cells

Lin, Chien Ju; Lee, Chin Cheng; Shih, Yu‐Lueng; Lin, Chang‐Ping; Wang, Sheng Hao; Chen, Thay Hsiung; Shih, Chwen Ming

doi:10.1371/journal.pone.0038706

Cited by 103 publications

(84 citation statements)

References 48 publications

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“…Induction of autophagy by TMZ has been documented in glioma cell lines and surgical specimens (11,12). In agreement with this, the current results showed that treatment with 100 µM TMZ induced autophagy as shown by a significant increase of AVOs and enhanced cleavage of LC3B (Fig.…”

Section: Tmz Treatment Induces Autophagy In Gliomasupporting

confidence: 90%

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Temozolomide induces autophagy via ATM-AMPK-ULK1 pathways in glioma

Zou

Wang

et al. 2014

Molecular Medicine Reports

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Abstract. Autophagy is a cytoprotective process, which occurs following temozolomide (TMZ) treatment, and contributes to glioma chemoresistance and TMZ treatment failure. However, the molecular mechanisms by which TMZ induces autophagy are largely unknown. In the current study, the ataxia-telangiectasia mutated (ATM) inhibitor KU-55933, adenosine monophosphate-activated protein kinase (AMPK) inhibitor compound C, and U87MG and U251 cell lines were employed to investigate the molecular mechanisms of TMZ-induced autophagy in glioma, and to evaluate the effects of autophagy inhibition on TMZ cytotoxicity. KU-55933 and compound C were observed to inhibit the activation of autophagy-initiating kinase ULK1 and result in a significant decrease of autophagy as indicated by depressed LC3B cleavage and acidic vesicular organelle formation. The activation of AMPK-ULK1 was ATM dependent. Autophagy inhibition via the AMPK inhibitor compound C augmented TMZ cytotoxicity as observed by depressed cell viability, increased γH2AX-marked double-strand breaks (DSBs) and elevated numbers of apoptotic glioma cells. In conclusion, TMZ induced autophagy via ATM-AMPK-ULK1 pathways. TMZ chemoresistance may therefore be overwhelmed by targeting AMPK, particularly for the treatment of O 6 -methylguanine DNA methyltransferase-negative gliomas.

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Section: Tmz Treatment Induces Autophagy In Gliomasupporting

confidence: 90%

“…Induction of autophagy by TMZ has been documented in glioma cell lines and surgical specimens, and inhibition of autophagy augments TMZ-induced apoptosis in glioma cells (11,12). However, the molecular mechanism by which TMZ induces autophagy is largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Temozolomide induces autophagy via ATM-AMPK-ULK1 pathways in glioma

Zou

Wang

et al. 2014

Molecular Medicine Reports

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“…45 Moreover, our data are consistent with the findings of other studies that autophagy could be triggered by ER stress. 46 Therefore, ER stress may cause autophagy to either protect or kill cells in different environments. However, the precise role of autophagy in ER stress is far from clear.…”

Section: Discussionmentioning

confidence: 99%

The roles of oxidative stress, endoplasmic reticulum stress, and autophagy in aldosterone/mineralocorticoid receptor-induced podocyte injury

Yuan

Zhao

et al. 2015

Laboratory Investigation

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Podocytes play an important role in the pathogenesis and progression of glomerulosclerosis. Recent studies indicate that aldosterone/mineralocorticoid receptor (MR) is a major contributor of chronic kidney disease (CKD) progression. Aldosterone/MR induces glomerular podocyte injury, causing the disruption of the glomerular filtration barrier and proteinuria. The present study investigated the mechanisms by which aldosterone/MR mediated podocyte injury, focusing on the involvement of oxidative stress, endoplasmic reticulum (ER) stress, and autophagy. We observed that aldosterone/ MR induced ER stress and podocyte injury both in vivo and in vitro. Blockade of ER stress significantly reduced aldosterone/ MR-induced podocyte injury. In addition, we found that ER stress-induced podocyte injury was mediated by CCAAT/ enhancer-binding protein (C/EBP) homologous protein (Chop). Interestingly, autophagy was also enhanced by aldosterone/MR. Pharmacological inhibition of autophagy resulted in increased apoptosis. Inhibition of ER stress significantly reduced aldosterone/MR-induced autophagy. In addition, the activation of ER stress increased the formation of autophagy, which protected podocytes from apoptosis. Moreover, we observed that the addition of ROS scavenger, N-acetyl cystein (NAC), blocked both ER stress and autophagy by aldosterone/MR. Collectively, these results suggest that oxidant stress-mediated aldosterone/MR-induced podocyte injury via activating ER stress, which then triggers both Chop-dependent apoptosis and autophagy to cope with the injury. These findings may guide us to therapeutic strategies for glomerular diseases.

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“…Studies have shown that high doses of temozolomide (1 mmol/L) and POH (1 mmol/L) activate cell death through ER stress pathway (5,31). To compare the efficacy of NEO212 and temozolomide, equimolar concentrations of these drugs were analyzed for expression of GRP78, CHOP, and cleaved PARP, proteins responsible for cytotoxicity initiated by ER stress.…”

Section: Neo212 Induces Glioma Cell Cytotoxicity Through Several Pathmentioning

confidence: 99%

NEO212, Temozolomide Conjugated to Perillyl Alcohol, Is a Novel Drug for Effective Treatment of a Broad Range of Temozolomide-Resistant Gliomas

Cho¹,

Wang²,

Jhaveri³

et al. 2014

Molecular Cancer Therapeutics

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Patients with glioblastoma multiforme (GBM), a malignant primary brain tumor, inevitably develop resistance to standard-of-care chemotherapy, temozolomide. This study explores the effects of the novel agent NEO212, a conjugate of temozolomide to perillyl alcohol, on temozolomide-resistant gliomas. NEO212 was tested for cytotoxic activity on three human temozolomide-resistant glioma cell lines, which were resistant to temozolomide based on overexpression of the base excision repair (BER) pathway, mismatch repair (MMR) deficiency, or overexpression of O 6 methyl-guanine-DNA methyltransferase (MGMT). BER expression was evaluated by Western blotting and PARP activity. MMR deficiency was determined by Western blotting and microsatellite instability. MGMT overexpression was evaluated by Western blotting and O 6 -benzylguanine (O 6 BG) inhibition. For in vivo evaluation of NEO212, temozolomide-resistant glioma cells were implanted into immune-incompetent mice, and NEO212 was administered. NEO212, at equimolar concentrations of temozolomide, was more cytotoxic for temozolomideresistant cells than temozolomide and not toxic to normal cells. NEO212-induced cell death in temozolomide-resistant glioma cells was independent of such mechanisms of resistance as high levels of MGMT, MMR deficiencies, or overexpression of BER proteins. NEO212 functions as a DNA alkylating agent, similar to temozolomide; however, this novel conjugate is unique for it may induce endoplasmic reticulum (ER) stress and inhibits autophagy. In vivo studies show that NEO212 reduces intracranial tumor growth and increases animal survival without significant toxicity. These results demonstrate that NEO212 is an effective drug against malignant gliomas that can be used for a broad range of newly diagnosed and temozolomide-resistant gliomas.

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Inhibition of Mitochondria- and Endoplasmic Reticulum Stress-Mediated Autophagy Augments Temozolomide-Induced Apoptosis in Glioma Cells

Cited by 103 publications

References 48 publications

Temozolomide induces autophagy via ATM-AMPK-ULK1 pathways in glioma

Temozolomide induces autophagy via ATM-AMPK-ULK1 pathways in glioma

The roles of oxidative stress, endoplasmic reticulum stress, and autophagy in aldosterone/mineralocorticoid receptor-induced podocyte injury

NEO212, Temozolomide Conjugated to Perillyl Alcohol, Is a Novel Drug for Effective Treatment of a Broad Range of Temozolomide-Resistant Gliomas

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