Sorafenib Induces Apoptosis and Inhibits NF-κB-mediated Anti-apoptotic and Metastatic Potential in Osteosarcoma Cells

Abstract

Background/Aim: Sorafenib, an oral multi-kinase inhibitor, has been shown to improve the outcome of patients with osteosarcoma (OS). However, the anti-OS effect and mechanism of sorafenib has not yet been fully understood. The main purpose of this study was to investigate the effect of sorafenib on apoptotic signaling and Nuclear Factor-ĸB (NF-ĸB)-mediated anti-apoptotic and metastatic potential in OS in vitro. Materials and Methods: The effect of sorafenib on apoptotic signaling transduction, anti-apoptotic, and metastatic potential of OS U-2 cells was verified with flow cytometry, trans-well invasion/migration, and western blotting assay. Results: Sorafenib induced the extrinsic and intrinsic apoptotic pathways. In addition, sorafenib reduced the invasion and migration ability of OS cells, induced NF-ĸB activation, and the expression of anti-apoptotic proteins and metastasisassociated proteins encoded by NF-ĸB target genes. Conclusion: Sorafenib led to stimulation of extrinsic/intrinsic apoptotic pathways and NF-ĸB inactivation in U-2 OS cells.Osteosarcoma (OS) is the common form of malignant bone tumor that frequently occurs in children and young adults (1). Conventional treatment strategies for osteosarcoma usually consist of surgery, chemotherapy, and radiotherapy, but the anti-OS efficacy of conventional treatment strategies is limited by chemo-radioresistance and metastasis (2, 3). Nuclear factor-ĸB (NF-ĸB), an oncogenic transcription factor, mediates chemo-radioresistance and metastasis by modulating the expression of anti-apoptotic and invasion-associated proteins encoded by NF-ĸB target oncogenes (4, 5). Suppression of NF-ĸB activation not only increases chemo-radiosensitivity but also reduces the metastatic potential of OS cells (6-9).In addition to improving chemo-radio resistance, how to effectively elicit cell death is also crucial for the treatment of OS. Apoptosis, a form of programmed cell death, is initiated by extrinsic (death receptor) and intrinsic (mitochondrial) signaling pathways, and is carried out by caspases (10). Treatment of OS cells and animal models with anticancer agents leads to 1251 *These Authors contributed equally to this study.

The anti-tumor effect of stigmasterol on sorafenib treated human breast cancer cell lines

“…NF-kB [22,23] and other transcription factors, such as FoxM1 [21], were suppressed; as a result of ERK inhibition. Downregulation of NF-kB in this study is consistent with previous studies on sorafenib [24] and stigmasterol [25]. Inhibition of transcription factor, FoxM1, leads to downregulation of VEGF.…”

Reinforcement of Sorafenib Anti-osteosarcoma Effect by Amentoflavone Is Associated With the Induction of Apoptosis and Inactivation of ERK/NF-κB

“…Inhibition of MMP-9 expression and VEGF signaling inhibit the growth and invasion of OS cells (21,22). Sorafenib was reported to reduce the protein levels of MMP-9 and VEGF as well as to suppress the migration and invasion of OS cells (23). Our data show that the sorafenib-induced inhibition of the invasion ability of OS cells was promoted by treatment with amentoflavone (Figure 1E and F).…”

Potential of overpowering Drugs Resistance in MC F-7/Adr cells by regulation of apoptotic pathways using sorafenib incorporating chitosan conjugated folic acid nanoparticles: An Experimental Study

“…These findings supported earlier research suggesting sorafenib promotes the rate of apoptosis in breast cancer. 40 . Furthermore, the targeted drug delivery system enhances this effect.…”