Abstract
Glioma is one of the most common types of primary brain tumors. Ivermectin (IVM), a broad-spectrum antiparasitic drug, has been identified as a novel anticancer agent due to its inhibitory effects on the proliferation of glioma cells in vitro and in vivo. However, the ability of IVM to induce autophagy and its role in glioma cell death remains unclear. The main objective of the present study was to explore autophagy induced by IVM in glioma U251 and C6 cells, and the deep underlying molecular mechanisms. In addition, we examined the effects of autophagy on apoptosis in glioma cells. In the present study, transmission electron microscopy (TEM), immunofluorescence, Western blot and immunohistochemistry were used to evaluate autophagy activated by IVM. Cell viability was measured by 3-(4,5-dimethylthiazol2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and colony formation assay. The apoptosis rate was detected by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Meanwhile, autophagy inhibition was achieved by using chloroquine (CQ). U251-derived xenografts were established for examination of IVM-induced autophagy on glioma in vivo. Taken together, the results of the present study showed that autophagy induced by IVM has a protective effect on cell apoptosis in vitro and in vivo. Mechanistically, IVM induced autophagy through AKT/mTOR signaling and induced energy impairment. Our findings show that IVM is a promising anticancer agent and may be a potential effective treatment for glioma cancers.
Highlights
Gliomas are the most common and lethal intracranial brain malignancies, and include astrocytomas, oligodendrogliomas and ependymomas [1,2]
The effects of IVM on autophagy in U251 and C6 cells were assessed by transmission electron microscopy (TEM)
Our research showed that IVM can cause a decrease in p-AKT (Ser473)/AKT and p-mTOR (S2448)/mTOR, which indicated that IVM inhibited AKT/mTOR signaling in U251 and C6 glioma cells, and the suppression of AKT/mTOR signaling may contribute to the activation of autophagy induced by IVM
Summary
Gliomas are the most common and lethal intracranial brain malignancies, and include astrocytomas, oligodendrogliomas and ependymomas [1,2]. These cancers eventually cause a widespread invasion throughout the brain and are resistant to traditional drugs and targeted therapeutic approaches. Current treatment modalities have only modest effect on patient outcomes [3,4]. It is urgent to explore more effective agents for glioma cancer patients in order to improve clinical outcome and quality of life. IVM has found a place in the clinical treatment of several other human diseases, including scabies, and has played an important role
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