SC‐1, a sorafenib derivative, shows anti‐tumor effects in osteogenic sarcoma cells

Abstract

Despite significant advances in the treatment of osteosarcoma (OS), overall survival rate of OS patients has remained relatively constant for over two decades and novel approaches are needed to further improve prognosis. Here, we report the anti-tumor effect of SC-1, a novel sorafenib derivative that closely resembles sorafenib structurally but is devoid of kinase inhibitory activity, on OS cells through mediation of signal transducer and activator of transcription 3 (STAT3). SC-1 showed similar effects to sorafenib on growth inhibition and apoptosis, and downregulated phospho-STAT3 (p-STAT3) at tyrosine 705 in all tested OS cell lines (U2OS, HOS, and 143B). Expression of STAT3-driven genes, including cylcin D1 and c-myc, were also repressed by SC-1. Ectopic expression of STAT3 in 143B cells abolished apoptosis in SC-1-treated cells. Inhibition of SHP-1 decreased SC-1-induced apoptosis. SC-1 upregulated the activity of SHP-1 in tested OS cell lines in a dose-dependent manner. Finally, SC-1 reduced 143B tumor growth significantly in vivo, which was associated with downregulation of p-STAT3 and upregulation of SHP-1 activity. These data demonstrate that SC-1 has clinical potential for the treatment of OS patients. ß

Repurposing FDA-approved drugs as therapeutics to treat Rift Valley fever virus infection

“…To further confirm that kinase activity of Raf was not required for RVFV infection, treatment with a sorafenib analog, SC-1, was performed. SC-1 differs from sorafenib in that SC-1 does not affect Raf kinase activity, but retains the ability to inhibit signal transducer and activator of transcription 3 (STAT3) (Yang et al, 2008 ; Wang et al, 2013 ). Thus cells treated with SC-1 will retain Raf kinase activity.…”

Signal Transducer and Activator of Transcription 3 as Molecular Therapy for Non–Small-Cell Lung Cancer

“…For in vitro studies, sorafenib and SC-1 [25][26][27] at various concentrations were dissolved in dimethyl sulfoxide (DMSO) and then added to cells in serum-free RPMI1640. Sodium vanadate, SHP-1, SHP-2, and protein-tyrosine phosphatase 1B (PTP1B) inhibitors were purchased from Merck (Calbiochem).…”

SMARCA4 regulates spatially restricted metabolic plasticity in 3D multicellular tissue

“…If left unchecked, excessive lipid peroxidation leads to programmed cell death known as ferroptosis 65 . Ferroptosis is agonized by the inhibitors of SLC7A11 erastin 65 and SC-1 66 ( Figure 5h ). Cell death via ferroptosis is also impaired by the antioxidants ferrostatin and liproxstatin 67 , as well as by the iron chelator deferoxamine 65 .…”