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

RADIATION
Radiation can cause similar treatment response to TMZ. Radiation treatment in GBM cells can induce
[52]
autophagy through the PI3K/AKT/mTOR pathway, ROS [50,51] and MST4 kinase-ATG4B signaling [Figure 2].
Inhibition of autophagy makes these cells susceptible to stimulation [53,54] . Moreover, it is reported that
[55]
GBM cells are susceptible to radiation following inhibition of MDA-9 expression . Radiation has various
effect to autophagy. Studies have indicated that the relatively radio-sensitive cells or small radiotherapy
fraction (2 Gy) displays enhanced autophagic flux, while more radio-resistant cells or largeer radiotherapy
[56]
fraction exhibited an inhibition of autophagic flux . Regarding the glioma stem-like cells, it was reported
the subsets were enhanced for autophagy after radiation to promote metabolism, anti-apoptosis and
+
[57]
stemness , while the other reports showed that CD133 cells or sphere cells from one patient have a lower
level of autophagy [58,59] . Notably, it is also found that CD133 glioma stem-like cells can be resensitized
+
to radiation treatment by using autophagy inhibitors (bafilomycin) or down-regulation of ATG protein
[60]
levels . Though the exact effect remains unclear, the association between autophagy, radiation, and the
stemness features is intriguing.
Whether targeting autophagy will benefit radiotherapy effect is also controversial. On one hand, a study
has found that autophagy in malignant glioma cells is a transition status promoting apoptotic cell death
[61]
following radiation, which can be reversed by suppressing autophagy function . On the other hand, from
[63]
[62]
the aspect of PI3K/AKT/mTOR signaling (it is active in most GBM patients ), Cerniglia et al. and Gil
[64]
del Alcazar et al. have indicated that NVP-BEZ235, a dual PI3K/mTOR inhibitor, can promote GBM cells
sensitive to radiation and up-regulate autophagy by directly affecting the function of DNA damage repair
(DNA-dependent protein kinase catalytic subunit and ATM kinase) and autophagy related proteins (ATG5
and Beclin1), respectively. The results demonstrated that there are different responses after administrating
[65]
the inhibitor and radiation leading to cell death. Furthermore, Zhuang et al. also reported that rapamycin
can lead to the differentiation of glioma stem-like cells, up-regulating the cell radiosensitivity and reducing
tumorgenesis through activation of autophagy. However, the application of the autophagy inducers on mice
experiment or clinical seems to be rare and limited in information [62,66] . In addition, most clinical trials
nowadays prefer the combination of autophagy inhibitors with radiochemotherapy but not radiotherapy
[67]
only . Therefore, the directions of future research must focus on further exploration of how radiation
induces autophagy (time point, tumor suppress genes, DNA damage repair and so on) and how the affected
autophagy changes the cell fate.

TUMOR TREATING FIELDS
OPtune, a tumor treating fields (TTFields) device, is used as an advanced GBM treatment with only
minor side effects noted in newly diagnosed or recurrent GBM patients. The device in combination with
[68]
TMZ increased the median overall survival by almost 5 months compared to the TMZ alone group . At
200 kHZ frequency, TTFields treatment has been reported to cause damaged mitosis and up-regulation of
[69]
autophagy . It is also found that the enhancement of autophagy is induced by TTFields treatment through
[70]
AMP-activated protein kinase (AMPK) signaling [Figure 2] and down-regulation of the pathway inhibits
the protective autophagy to reduce TTFields-induced acquired resistance. By combining with sorafenib,
a multi-kinase inhibitor that can induce autophagy in prostate cancer cells through increased levels of
[71]
LC3 , the device exhibited enhanced autophagy and more inhibited tumor behavior to promote a better
[72]
therapeutic strategy . Regarding the mechanism, it was reported that TTFields can suppress DDR in non-
[73]
small cell lung cancer cell lines and the combination of radiation can inhibit DNA damage repair in
[74]
glioma cell lines . Furthermore, it is found that TTFields can cause ROS production to promote apoptosis
[72]
in the cell line study . This may have impact in inducing the clearance of damaged mitochondria
[75]
(mitophagy) . It is not clear, however, whether TTFields-increased autophagy is associated with inhibition
of DNA damage repair. Further explorative experiments are thus needed to elucidate the mechanism and
the role of autophagy in the disease-controlling mechanism of the device.