Antiglioma effects of cytarabine on leptomeningeal metastasis of high-grade glioma by targeting the PI3K/Akt/mTOR pathway

Abstract

Leptomeningeal metastasis (LM) of high-grade glioma is a highly lethal disease requiring new effective therapeutic measures. For both de novo or relapsed glioma with LM, intrathecal cytarabine chemotherapy is not frequently used for first-line and relapse protocols. We encountered a clinical case demonstrating effective application of cytarabine in high-grade glioma with LM, prompting us to explore the effects of cytarabine on malignant glioma and molecular mechanisms of such effects through in vivo and in vitro experiments. The U87 cell line was selected to represent human glioma for studies. Cell viability was measured by MTT assay, plate colony formation assay, and trypan-blue dye exclusion test. Apoptosis was assessed by flow cytometry. Protein expression levels were detected by Western blot assay and immunohistochemistry. mRNA expression was examined by quantitative real-time reverse transcription polymerase chain reaction. Cytarabine inhibited tumor growth during the in vivo experiment. The present study confirmed that cytarabine inhibits proliferation and promotes apoptosis of U87 cells, and molecular analysis of this effect showed that cytarabine significantly reduces expression of phosphatidylinositol 3-kinase/serine/threonine kinase also known as the protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR) pathway, Ki-67, BCL2, and 4-1BB, and upregulates Bax and cleaved caspase-3. Our findings indicated that intrathecal administration of cytarabine manifests potential in prophylaxis and treatment of malignant glioma with LM. Effective medications for high-grade glioma with LM should contain cytarabine.

Downregulation of hsa_circ_0004543 Activates oxLDL-Induced Vascular Endothelial Cell Proliferation and Angiogenesis

“…Following phosphorylation by PI3K, AKT acts on the downstream target proteins caspase-9, Bad, glycogen synthase kinase-3β, and eNOS. AKT is also involved in cell proliferation and apoptosis ( Yoon, 2017 ; Zhao et al, 2017 ). Nitric oxide (NO) is not only an endogenous anti-atherosclerotic factor, but also an important indicator of endothelial cell function.…”

The Gαh/phospholipase C-δ1 interaction promotes autophagosome degradation by activating the Akt/mTORC1 pathway in metastatic triple-negative breast cancer

“…Recent reports have demonstrated that the activation of the Akt/mTOR pathway induced by the long noncoding RNAs OECC [ 23 ] and MetaLnc9 [ 24 ] and the transmembrane 7 superfamily member 4 [ 25 ] promotes metastatic progression; conversely, the suppression of the Akt/mTOR pathway in the presence of the ferulic acid derivative FXS-3 [ 26 ], cardamonin [ 27 ] and microRNA-520a-3p [ 28 ] inhibits the metastatic potential of lung cancer cells. Accordingly, the association of the Akt/mTOR pathway with metastatic progression has been reported in other cancer types, including colorectal cancer [ 29 – 31 ], hepatocellular carcinoma [ 32 – 34 ], endometrial cancer [ 35 , 36 ], ovarian cancer [ 37 ], gastric cancer [ 38 – 40 ], melanoma [ 41 ], glioma [ 42 , 43 ], pancreatic ductal adenocarcinoma [ 44 ], nasopharyngeal carcinoma [ 45 , 46 ], osteosarcoma [ 47 – 50 ], renal cell carcinoma [ 51 – 53 ] and prostate cancer [ 54 – 56 ]. In breast cancer, synaptopodin-2 [ 57 ] and caveolin-1 [ 58 ] have been shown to modulate Akt/mTOR-regulated metastatic progression.…”

Identification of Grade-associated MicroRNAs in Brainstem Gliomas Based on Microarray Data

“…Knockdown of HIF-1α in glioma cells reduces migration and impairs their ability to form tumour spheres 35 . Recently, evidence suggested that cytarabine attenuates the leptomeningeal metastasis of high-grade glioma by targeting the PI3K/Akt/ mTOR pathway 36 . The Hippo signalling pathway is considered a key player in the regulation of tumourigenesis, and inactivating the Hippo signalling pathway enhances stem cell-like phenotypes in glioblastoma 37 , 38 .…”