Table 4.

In vitro studies of autophagy inducers on the TMZ anti-glioblastoma activity

Cell lines	Therapeutic methods (concentration /exprosure time)	Major findings	Interpretation	Reference
Human U87/EGFR and U251 cells	TMZ 5 and 50μM/48-72 hours dasatinib 200 nM/48-72 hours	Augmentation of Dasatinib-Induced Autophagy in combination with Temozolomide.	TKI increased autophagic cell death and sensitivity of TMZ therapy.	[93]
Human T98G and U373 cells	TMZ (300 μM) was added to the culture immediately after IR/ time: N/A rapamycin 0.1, 0.5, and 1 mM/24 hours	Autophagy-associated cell death sensiyized glioma cells to combined radiotherapy/ TMZ treatments.	Rapamycin-mediated autophagy promoted malignant glioma cell death induction after combined radiotherapy/TMZ treatments.	[23]
Human U251, U87, and T98G cells	TMZ 25 μM/24 hours IR 6Gy/6 hours PI103 0.4 μM/24 hours	A dual inhibitor of class I PI3K/mTOR, PI103, increased the cytotoxic effect of radiation therapy plus TMZ.	Enhanced radiosensitizing effects of TMZ by PI103 induced the autophagy and apoptosis, and reversed the EMT.	[100]
Human NCH82 cells	TMZ 500 μM/72 hours SKI 10 μM/72 hours	SKI could sensitize GBM cells to TMZ treatment.	Combination of TMZ and SKI resulted in autophagic flux increased and further induction of cell death potentiation.	[105]
Human T98G and SF295 cells	TMZ 25μM/96 hours VPA 1mM/96 hours	VPA increased the sensitivity of glioma cells to TMZ.	VPA enhanced the activities of TMZ on glioma cells through blocking cell cycle and promoting autophagy.	[109]
Human U87, U343, LNT-229, and MZ-54 cells	TMZ100μM/96 hours (−)-Gossypol 15μM/48 hours	Pan-Bcl-2 inhibitors augmented the action of TMZ on apoptosis-resistant malignant glioma cells.	Pan-Bcl-2 inhibitors (−)-Gossypol induced caspase-independent, autophagic cell death when combined treatment with TMZ.	[112]
Human T98G and U373 cells	TMZ 100μM/48 hours EGFR SiRNA 1μM/72 hours	EGFR interfering resulted in an increase of TMZ cytotoxicity in TMZ-resistant GBM cells.	EGFR SiRNA inhibited the pro-death autophagy and sensitized GBM cells to subsequent TMZ treatments	[97]
Human U251 cells	TMZ 100 μM/72 hours Nrf2 shRNA N/A	Combination of TMZ and the knockdown of Nrf2 could enhance the antitumor effects of TMZ in GBM.	Knockdown of Nrf2 by shRNA enhanced autophagy induced by TMZ.	[117]
Human U87, T98G, and HG19 cells	TMZ 25-75μM/72 hours THC 0.9μM/72 hours	Coadministration of TMZ with THC exerted a strong antitumoral action in glioma cells.	Combined administration of THC and TMZ enhanced autophagy-mediated apoptosis in tumor cells.	[86]
Human T98G and U251 cells	TMZ 300-500 μM/24 hours WA 0.5-2μM/24 hours	Combination treatment with WA and TMZ resulted in resensitization of TMZ-resistance	Withaferin A resensitizes TMZ-resistant GBM cells to TMZ through MGMT depletion	[87]
Human U87 and U373 cells	TMZ 100 μM/24 hours oncolytic adenovirus 100 vp per cell/24 hours	Oncolytic adenovirus led to improved efficacy of TMZ treatment against a panel of glioma cell lines.	Combination of oncolytic adenovirus with TMZ increased tumor cell autophagy and apoptosis-mediated cell death.	[90]
Rat RG2 cells	TMZ 100 μM/48 hours PTx 20 ng/ml /48 hours	PTx has the potential to be useful as an adjunct to TMZ chemotherapy on glioma.	Concomitant treatment with TMZ and PTx elicited autophagic cell death in vitro and increased the survival in RG2 glioma model.	[122]