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Targeting off-target effects: endoplasmic reticulum stress and autophagy as effective strategies to enhance temozolomide treatment

Authors He Y, Su J, Lan B, Gao Y, Zhao J

Received 15 November 2018

Accepted for publication 1 February 2019

Published 7 March 2019 Volume 2019:12 Pages 1857—1865


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Andrew Yee

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Geoffrey Pietersz

Yichun He,1 Jing Su,2 Beiwu Lan,1 Yufei Gao,1 Jingxia Zhao3

1Department of Neurosurgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China; 2Department of Pathophysiology, Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China; 3Experimental Teaching Center, School of Nursing, Jilin University, Changchun, Jilin, China

Abstract: Glioblastoma multiforme (GBM) is the most common and aggressive adult primary central nervous system tumor. Unfortunately, GBM is resistant to the classic chemotherapy drug, temozolomide (TMZ). As well as its classic DNA-targeting effects, the off-target effects of TMZ can have pro-survival or pro-death roles and regulate GBM chemoradiation sensitivity. Endoplasmic reticulum (ER) stress is one of the most common off-target effects. ER stress and its downstream induction of autophagy, apoptosis, and other events have important roles in regulating TMZ sensitivity. Autophagy is an evolutionarily conserved cellular homeostasis mechanism that is closely associated with ER stress-induced apoptosis. Under ER stress, autophagy cannot only remove misfolded/unfolded proteins and damaged organelles and degrade and inhibit apoptosis-related caspase activation to reduce cell damage, but may also promote apoptosis dependent on ER stress intensity. Although some protein interactions between autophagy and apoptosis and common upstream signaling pathways have been found, the underlying regulatory mechanisms are still not fully understood. This review summarizes the possible mechanisms underlying the current known off-target roles of ER stress and downstream autophagy in the regulation of cell fate and evaluates their role in TMZ treatment and their potential as therapeutic targets.

Keywords: autophagy, apoptosis, chemotherapy resistance, temozolomide, glioma, endoplasmic reticulum stress

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