Therapeutic Potential of Autophagy in Glioblastoma Treatment With Phosphoinositide 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin Signaling Pathway Inhibitors

Abstract

Glioblastoma (GB) is the most malignant and aggressive form of brain tumor, characterized by frequent hyperactivation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. PI3K/AKT/mTOR inhibitors have a promising clinical efficacy theoretically. However, strong drug resistance is developed in GB against the PI3K/AKT/mTOR inhibitors due to the cytoprotective effect and the adaptive response of autophagy during the treatment of GB. Activation of autophagy by the PI3K/AKT/mTOR inhibitors not only enhances treatment sensitivity but also leads to cell survival when drug resistance develops in cancer cells. In this review, we analyze how to increase the antitumor effect of the PI3K/AKT/mTOR inhibitors in GB treatment, which is achieved by various mechanisms, among which targeting autophagy is an important mechanism. We review the dual role of autophagy in both GB therapy and resistance against inhibitors of the PI3K/AKT/mTOR signaling pathway, and further discuss the possibility of using combinations of autophagy and PI3K/AKT/mTOR inhibitors to improve the treatment efficacy for GB. Finally, we provide new perspectives for targeting autophagy in GB therapy.

Tumor-derived exosomal microRNA-7-5p enhanced by verbascoside inhibits biological behaviors of glioblastoma in vitro and in vivo

“… 19 Inhibition of the PI3K/Akt/mTOR signaling pathway has a promising clinical efficacy since activation of autophagy by the PI3K/Akt/mTOR inhibitors can enhance treatment sensitivity and trigger cell survival once drug resistance occurs in cancer cells. 37 More importantly, miR-7-5p was verified to target EGFR, which has the capability to regulate gastric cancer cell proliferation and apoptosis through regulation of downstream pathways. 18 Notably, reduction in the miR-7-5p expression contributes to the increase of EGFR expression and activation of the PI3K/AKT/c-Myc signaling pathway in the context of glioma.…”

N6-Methyladenosine Methyltransferase METTL14-Mediated Autophagy in Malignant Development of Oral Squamous Cell Carcinoma

“…Rapamycin is a new macrolide antibiotic and an anti-cancer drug certified by the FDA ( 26 ). Research has shown that rapamycin can prevent or delay the occurrence of tumours, including colon cancer ( 27 ), glioblastoma ( 28 ), renal cell cancer ( 29 ), and ovarian cancer ( 30 ). At present, a rapamycin phase III clinical trial has been completed, and its safety and therapeutic effects have been confirmed.…”

Pemafibrate Pretreatment Attenuates Apoptosis and Autophagy during Hepatic Ischemia-Reperfusion Injury by Modulating JAK2/STAT3β/PPARα Pathway

“…The release of ROS could stimulate autophagy and apoptosis in the liver [9,10]. We determined Beclin-1 and LC3 as well as P62 (autophagy markers) and Bcl-2 family as well as Caspase family (apoptosis markers) by qRT PCR, WB, and immunohistochemistry [13,28]. We found that PEM injection enabled the injured liver to produce more P62 and Bcl-2 and reduce Beclin-1, LC3, Bax, Caspase 9, and Caspase 3.…”