Anlotinib combined with temozolomide suppresses glioblastoma growth via mediation of JAK2/STAT3 signaling pathway

Abstract

Purpose Anlotinib 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). Methods Cell 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. Results Anlotinib 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. Conclusion Anlotinib 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.

RETRACTED: The efficacy and adverse effects of anlotinib in the treatment of high-grade glioma: A retrospective analysis

“…Its antiangiogenic effect is better than that of sunitinib, sorafenib, and nintedanib, which are the three major clinical antiangiogenic drugs (22). TMZ enhances the anti-glioblastoma effects of anlotinib through the same signaling pathway, indicating that anlotinib can serve as a therapeutic option for glioblastoma (23).…”

Roles of STAT3 in the pathogenesis and treatment of glioblastoma

“…The expression levels of Beclin-1 and microtubule-related protein 1 light chain 3B (LC3B) was increased to induce autophagy and apoptosis in GBM cells and to inhibit their invasion and metastasis. Temozolomide can effectively enhance the antitumor ability of anlotinib, and the combination of the two drugs inhibited JAK2/STAT3/VEGFA signaling more effectively than either drug alone under in vitro conditions (Xu et al, 2022).…”

Synergistic Effects of A Combined Treatment of Glioblastoma U251 Cells with An Anti-miR-10b-5p Molecule and An AntiCancer Agent Based on 1-(3′,4′,5′-Trimethoxyphenyl)-2-Aryl-1H-Imidazole Scaffold

“…It should be underlined that combined treatments appear of great interest in the development of anticancer approaches [ 7 , 8 , 9 , 10 , 11 , 12 ], since they are expected to obtain the same biological or therapeutic effect using lower concentrations of two or more drugs, thereby limiting side effects [ 58 ]. Importantly, combined therapy might be of great importance in the management of Glioblastoma (GBM), a lethal malignant tumor needing novel therapeutic options.…”

“…Combined treatment might be of great interest in order to develop effective therapeutic protocols for glioblastoma [ 7 , 8 , 9 , 10 , 11 , 12 ]. In this respect, we have recently reported a possible combined therapeutic approach for GBM based on the use of microRNA inhibitors and anti-GBM molecules.…”