Table 2.

In vivo studies of autophagy inhibitors and inducers on the TMZ anti-glioblastoma activity

Effect of autophagy modulation	Subject	Agent regimen	Major findings	Interpretation	Reference
cytoprotective role	Xenografts of human U87 MG GBM cells in male athymic nu/nu mice	CQ 10 mg/kg + TMZ 5 mg/kg given by oral gavage for 48 hours with water.	CQ enhances the cytotoxic effects of TMZ by blocking autophagy.	CQ in combination with TMZ significantly increased the amounts of LC3B-II, CHOP/GADD-153, and cleaved PARP.	[48]
	Xenografts of human U87 GBM cells in athymic nude mice	50 mg/kg of QNX for 24 hours; 25 mg/kg QN, CQ, MFQ, or QNX for 48 hours.	QBAs, a novel class of autophagy inhibitors, are holding the promise for the coadministration treatment of gliomas.	QNX selectively accumulates in tumor cell vacuoles. QBAs have the ability to induce ER stress potentially leading to apoptosis.	[49]
	Xenografts of human U87 MG GBM cells in nude mice	Resveratrol 12.5 mg/kg + TMZ 10 mg/kg injected intraperitoneally for 12 days.	Resveratrol increases the effect of TMZ in glioma xenografts by reduceing tumor volumes.	Coadministration of resveratrol and TMZ suppressing ROS/ERK-mediated autophagy and subsequently inducing apoptosis	[42]
	Xenografts of SJG2 pediatric GBM in NOD-SCID mice	MA 100 mg/kg + TMZ 65 mg/kg given by oral gavage for two weeks.	Combination had a significant increase in survival.	ATM-MPG axis will lead to improved treatment of alkylating agent-resistant tumors.	[43]
Autophagy-associated cell death	Xenografts of human U87 and T98 GBM cells in nude mice	THC 15 mg/kg + TMZ 5 mg/kg injected peritumorally for 14 days in 100 mL of PBS supplemented with 5 mg/mL defatted and dialyzed BSA.	Combined treatment with THC and TMZ strongly reduces the growth of glioma xenografts.	Combined treatment with THC and TMZ enhances autophagy-mediated cell death.	[86]
	Xenografts of human U87 MG GBM cells in female BALB/c nu/nu mice	AdWT or CRAd-S-pk7 3×109 vp in 5 μl + TMZ 70 or 10 mg/kg in 100 μl injected with five consecutive intraperitoneal.	In which 90% of the mice with intracranial tumours were long-term survivors after treatment with TMZ and CRAd-S-pk7.	As both LC3 and cleaved Caspase-3 expressed, both autophagy and apoptosis are responsible for cell death.	[90]