Sorafenib inhibits vascular endothelial cell proliferation stimulated by anaplastic thyroid cancer cells regardless of BRAF mutation status

Abstract

Anaplastic thyroid cancer (ATC) is a rare refractory disease, frequently associated with BRAF mutations and aberrant vascular endothelial growth factor (VEGF) secretion. The antitumor effects of sorafenib were evaluated, and its mechanisms of action were investigated. Four human ATC cell lines were used: OCUT-4, which possesses a BRAF mutation; OCUT-6 and ACT-1, which carry NRAS mutations; and OCUT-2, which possesses mutations in BRAF and PI3KCA. The viability of Sorafenib was evaluated by MTT assay. In order to examine the inhibitory effect of Sorafenib on intracellular signal transduction, expression of mitogen-activated protein kinase kinase was examined by western blotting. In addition, cell cycle analysis was performed using flow cytometry. The inhibitory effects of sorafenib on the growth of ATC cells and human umbilical vein endothelial cells (HUVECs) stimulated with conditioned media from ATC cells were examined. Sorafenib inhibited the viability of OCUT-4 more effectively than other ATC cell lines; these effects may have been mediated cytostatically by suppressing mitogen-activated protein kinase kinase phosphorylation. Conversely, similar suppression was not observed in OCUT-6 cells, which possess an NRAS mutation. The four cell lines secreted different quantities of VEGF, and the proliferation of HUVECs was differentially stimulated by their conditioned media. Both anti-VEGF antibody and sorafenib prevented this stimulation of proliferation. In conclusion, sorafenib more effectively inhibited RAF-generated growth signals in ATC cells compared with signals generated by its upstream gene, RAS. ATC cells stimulated the growth of HUVECs via humoral factors, including VEGF; this effect was clearly inhibited by sorafenib. The present findings highlighted the potential of sorafenib for the treatment of ATC and provided insight into its mechanism of action.

Zebrafish Models of Cancer Therapy-Induced Cardiovascular Toxicity

“…Additionally, cancer can cause unregulated vessel growth by modulating angiogenesis and vasculogenesis, aiding in the proliferation and metastatic spread of cancerous cells. Several cancer therapies, such as the VEGF pathway inhibitors sorafenib and sunitinib, are effective at targeting these processes in cancerous tissue, but also disrupt normal angiogenic processes and are associated with cardiovascular toxicity in patients [ 30 , 31 , 32 ]. There are several existing in vitro models for angiogenesis, such as proliferation assays, tubule formation assays, and organ explant assays [ 33 , 34 , 35 , 36 , 37 , 38 , 39 ].…”

Longitudinal assessment of B-RAF V595E levels in the peripheral cell-free tumor DNA of a 10-year-old spayed female Korean Jindo dog with unresectable metastatic urethral transitional cell carcinoma for monitoring the treatment response to a RAF inhibitor (sorafenib)

“…In human patients, the efficacy of molecular-targeted therapy has been shown to be limited and to depend on the presence of specific genetic alterations in cancer cells. 5 B-Raf (Rapidly accelerated fibrosarcoma) proto-oncogene (B-RAF) mutation is widely known as an important driver of the aberrant proliferation of cancer cells. 6,7,8 A B-RAF-targeting inhibitor has already been established as an important therapeutic agent in several types of human cancers.…”

Recent advances in the management of anaplastic thyroid cancer

“…Sorafenib activity against ATC cells has been proved both in vitro and in vivo experiments. In the former, Sorafenib reduced proliferation and enhanced apoptosis in several ATC cell lines, regardless of BRAF mutation status [ 39 , 40 ]; in the latter, Sorafenib proved effective in inhibiting the growth of orthotopic ATC xenografts in mice, thus improving their survival [ 39 ]. Preclinical studies suggested that several drugs may exert synergic effect with Sorafenib in reducing ATC cells growth, including metformin [ 41 ].…”