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Page 4 of 10 Chien et al. J Cancer Metastasis Treat 2019;5:66 I http://dx.doi.org/10.20517/2394-4722.2019.016

Figure 2. The schematic diagram demonstrates that in primary or recurrent GBM patients, the standard regimens consists of TMZ,
radiation, TTFields, bevacizumab, etoposide and cisplatin, which enhance cell stemness, metabolism (energy), anti-apoptosis and DNA
repair to acquire therapeutic resistance through the signaling pathways of DDR, ROS, hypoxia, AKT/mTOR, MST4 kinase, AMPK and RB.
Nowadays, the inhibitors of late-stage autophagy, such as CQ or its analogs, have been tested in clinical trials of GBM patients. TMZ:
temozolomide; GBM: glioblastoma; TTFields: tumor treating fields; ROS: reactive oxygen species; DDR: DNA damage response; AMPK:
AMP-activated protein kinase; RB: retinoblastoma; CQ: chloroquine

[40]
glucose starvation condition causes GBM cell quiescence, survival and chemoresistance and complex
I linked oxidative phosphorylation is required to maintain mitochondrial respiration (electron transfer
[41]
system) through autophagy regulation . Furthermore, presence of glioma stem-like cells may have crucial
[42]
role in acquiring resistance . An emerging concept in cancer biology suggests these specific subgroups
[42]
with stemness features are responsible for acquisition of resistance . The stem cells are characterized
[43]
by self-renewal and multipotent abilities . These allow cells to be resistant to standard therapy, and are
[42]
associated with the treatment outcome . In glioma stem-like cells, autophagy-associated proteins, i.e.,
DNA Damage Regulated Autophagy Modulator 1 and p62, can regulate the cell migration and invasion by
modulating energy metabolism (ATP) and affect mitochondrial morphology by regulating mitochondrial
[44]
fusion . Some studies have indicated that autophagy can regulate epithelial-to-mesenchymal transition [45]
and the capabilities of migration and invasion in those cells under nutrient deprivation are damaged when
[46]
autophagy is activated through regulation of ATG proteins or beclin 1 . However, it was found that
[47]
TMZ treatment plus autophagy inhibitor could suppress cell migration and invasion , suggesting further
investigation was needed to determine the role of TMZ-induced autophagy in this aspect. Moreover,
stemness features in the glioma stem-like cells are reduced by autophagy inhibition and apoptosis is
[48]
enhanced by blockage of autophagy . Recently, it is found that the blockage of autophagy up-regulates the
[49]
TMZ-sensitivity in these stem-like cells through metabolic dysfunction-related ferroptosis in the stem-
like cells, demonstrating the close correlation between autophagy and metabolism. In summary, application
of these the explains how the disease is capable of surviving TMZ toxicity regardless of MGMT status.