Send to

Choose Destination
Onco Targets Ther. 2019 Mar 7;12:1857-1865. doi: 10.2147/OTT.S194770. eCollection 2019.

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

Author information

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


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.


apoptosis; autophagy; chemotherapy resistance; endoplasmic reticulum stress; glioma; temozolomide

Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Publication type

Publication type

Supplemental Content

Full text links

Icon for Dove Medical Press Icon for PubMed Central
Loading ...
Support Center