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Page 6 of 10 Chien et al. J Cancer Metastasis Treat 2019;5:66 I http://dx.doi.org/10.20517/2394-4722.2019.016

BEVACIZUMAB
Bevacizumab can directly promote apoptosis and antiangiogenesis by regulating the associated proteins
in GBM cells [19,76] . This drug has been reported to cause resistance in the cells through suppressing
[76]
[19]
AKT-mTOR signaling or through inducing hypoxia-inducible factor-1α/AMPK pathway to
increase autophagy influx [Figure 2]. It was also reported that bevacizumab could cause a hypoxia
microenvironment, which in turn, was related to enhanced autophagy [77,78] . Thus, inhibition of the
autophagy process was postulated to resensitize bevacizumab to GBM cells.

Up-regulation of glucose metabolism before autophagy induction was observed in bevacizumab-treated
[79]
GBM cell lines . Further investigation is needed to link the mechanism between autophagy and the cell
metabolism after the treatment. It was also noted that bevacizumab can induce autophagy in glioma stem-
like cells by enhancing VEGF-independent angiogenesis (vasculogenic mimicry, an alternative vasculature)
[80]
through KDR/VEGFR-2 phosphorylation, which the formation is closely related with GBM resistance .
This highlights the therapeutic value of autophagy-inhibiting strategies in regard with the anti-angiogenesis
therapy.

ETOPOSIDE
Etoposide (VP-16) treatment has been reported to induce autophagy, thereby increasing the therapeutic
resistance in GBM cells [81,82] . The drug is a topoisomerase II inhibitor that also enhances autophagy
by modulating though retinoblastoma protein (RB) [81] [Figure 2]. Down-regulation of RB can inhibit
autophagy by preventing autophagosomes fusion from lysosome and promoting cell death in GBM cells
[81]
and glioma stem-like cells . Furthermore, knockdown of RB can enhance apoptotic cell death and up-
regulate the immunostaining intensity of γ-H2AX (a DNA double-strand break marker) induced by
[81]
etoposide . Earlier studies have demonstrated a close link between etoposide-induced autophagy, RB, and
DNA damage.

CISPLATIN
Cisplatin (CDDP) is a DNA alkylating agent that is widely used for human malignant tumors including
[83]
GBM . CDDP-associated resistance often develops through autophagy induction in multiple cancer cell
types [84-87] . In cervical cancer cells, it is found that blockage of autophagy can increase CDDP-induced
[88]
cytotoxicity via endoplasmic reticulum stress . One study indicated that autophagy was associated with CDDP
[87]
resistance in GBM and down-regulation of RB suppressed autophagy induced by CDDP [Figure 2]. Moreover,
it was found that CDDP could induce long non-coding RNA to suppress CDDP-induced autophagy, which
[89]
promoted apoptosis in GBM cells . CDDP could also enhance the level of death receptor (DR5), directing
glioma stem-like cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) apoptotic
[90]
pathway . TRAIL, on the other hand, was reported to enhance the expression of autophagy leading to
[91]
resistance of breast cancer cells, and blockage of autophagy could reduce the resistance . The association
between autophagy and TRAIL in GBM has thus been inferred. In addition, the mechanism of DNA repair
induced by CDDP could promote resistance of GBM cells via the Jun kinase/stress-activated protein kinase
[92]
signaling pathway . Further experiments are required to verify whether autophagy is related to the DNA
repair induced by CDDP.

CARMUSTINE
Another DNA damaging nitrosoureas agent carmustine (BCNU) is reported to promote ROS-mediated
[93]
autophagic cell death in solid tumor cells in combination with arsenic trioxide . In terms of the role
of ROS in the drug reaction, it was supportively reported that in human glioma cell line U98MG, the
overexpression of Nrf 2, an anti-oxidant transcriptional factor, could reduce the carmustine-induced