Abstract
PurposeAnlotinib protects against carcinogenesis through the induction of autophagy and apoptosis. The current study evaluated the role and molecular mechanisms of anlotinib in glioblastoma, and the effects of anlotinib in combination with temozolomide (TMZ).MethodsCell Counting Kit-8 and colony-forming assays were used to evaluate cell viability. Cell migration and invasion were assessed by wound-healing, Transwell migration, and Matrigel invasion assays. Cellular apoptosis and cell cycle analysis were determined by flow cytometry. Angiogenesis was assessed using human umbilical vein endothelial cells (HUVECs). Vascular endothelial growth factor A (VEGFA) was measured by enzyme-linked immunosorbent assay. Protein expression was determined by western blotting or immunofluorescence staining. The in vivo anti-glioblastoma effect was assessed with live imaging of tumor xenografts in nude mice.ResultsAnlotinib restricted the proliferation, migration, and invasion of glioblastoma cells in a dose-dependent manner. Tumor supernatant from glioblastoma cells treated with anlotinib inhibited angiogenesis in HUVECs. Anlotinib induced autophagy in glioblastoma cells by increasing Beclin-1 and microtubule-associated protein 1 light chain 3B (LC3B) levels. Mechanistically, anlotinib inhibited the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3)/VEGFA signaling pathway. STAT3 inhibition by S3I-201 decreased VEGFA and suppressed cellular proliferation and movement. TMZ enhanced the anti-glioblastoma ability of anlotinib. Finally, anlotinib inhibited tumor growth and JAK2/STAT3/VEGFA signaling in xenografts.ConclusionAnlotinib exerts anti-glioblastoma activity possibly through the JAK2/STAT3/VEGFA signaling pathway. TMZ potentiated the anti-glioblastoma effect of anlotinib via the same signaling pathway, indicating the potential application of anlotinib as a treatment option for glioblastoma.
Highlights
Gliomas are the most common primary intracranial tumor
Anlotinib suppressed the proliferation of glioblastoma cells
Cells were treated with anlotinib (0, 1.25, 2.5, 5, 10, and 20 μM) for 24, 48, or 72 h, and 0.1% dimethyl sulfoxide (DMSO) served as the vehicle control
Summary
Gliomas are the most common primary intracranial tumor. More than half of all gliomas are malignant in adults, and comprise more than 80% of malignant tumors in the central nervous system. Glioblastoma multiforme (GBM) accounts for more than 50% of total gliomas [1]. The standard treatment option of GBM is surgery accompanied by chemotherapy and radiotherapy. Despite therapeutic advances including accurate surgical techniques and additional chemotherapeutic options, the median survival from the time of diagnosis is only 12–15 months [2], and the 5-year survival rate is below 5% [3]. According to the currently accepted standard protocols, temozolomide (TMZ) is the first-line chemotherapeutic agent for GBM and increases survival to approximately 14 months [4]. New strategies for the treatment of GBM are urgently required
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