NSK-01105, a Novel Sorafenib Derivative, Inhibits Human Prostate Tumor Growth via Suppression of VEGFR2/EGFR-Mediated Angiogenesis

Abstract

The purpose of this study is to investigate the anti-angiogenic activities of NSK-01105, a novel sorafenib derivative, in in vitro, ex vivo and in vivo models, and explore the potential mechanisms. NSK-01105 significantly inhibited vascular endothelial growth factor (VEGF)-induced migration and tube formation of human umbilical vein endothelial cells at non-cytotoxic concentrations as shown by wound-healing, transwell migration and endothelial cell tube formation assays, respectively. Cell viability and invasion of LNCaP and PC-3 cells were significantly inhibited by cytotoxicity assay and matrigel invasion assay. Furthermore, NSK-01105 also inhibited ex vivo angiogenesis in matrigel plug assay. Western blot analysis showed that NSK-01105 down-regulated VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR2) and the activation of epidermal growth factor receptor (EGFR). Tumor volumes were significantly reduced by NSK-01105 at 60 mg/kg/day in both xenograft models. Immunohistochemical staining demonstrated a close association between inhibition of tumor growth and neovascularization. Collectively, our results suggest a role of NSK-01105 in treatment for human prostate tumors, and one of the potential mechanisms may be attributed to anti-angiogenic activities.

A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

“…Treatment with sorafenib was previously shown to inhibit the invasion of PC3 cells. 83 We demonstrated that free or micellar nilotinib and sorafenib decreased the migration and invasion of PC3 cells. However, only the micellar nilotinib reduced MMP-9 secretion, as assessed by zymography and Western blot.…”

Potential lymphangiogenesis therapies: Learning from current antiangiogenesis therapies—A review

“…This supports an intimate interplay between the VEGF and EGF pathways in promoting cancer progression through angiogenesis. A novel sorafenib derivative that targets both VEGFRs and EGFRs has been shown to be efficacious in vitro against prostate tumors . In addition, in animal xenograft models of nonsmall cell lung cancer, therapies targeting both VEGFR and EGFR for tumor treatment are more effective than those targeting either receptor family alone .…”

“…A novel sorafenib derivative that targets both VEGFRs and EGFRs has been shown to be efficacious in vitro against prostate tumors. 163 In addition, in animal xenograft models of nonsmall cell lung cancer, therapies targeting both VEGFR and EGFR for tumor treatment are more effective than those targeting either receptor family alone. 164,165 Therefore, monoclonal antibodies such as cetuximab and receptor tyrosine kinase inhibitors such as erlotinib that target EGFRs represent a two-pronged approach to cancer therapy by inhibiting tumor growth directly and indirectly by blocking proliferation of the tumor vasculature ( Figure 6).…”

Discovery of biphenyl-aryl ureas as novel VEGFR-2 inhibitors. Part 4: Exploration of diverse hinge-binding fragments

“…Compound (2) was afforded by coupling of bis(pinacolato)diboron with bromide (1) without further purification. 16 Then critical intermediate (5) was prepared from (2) and (3), or compound (1) and (4) by classical Pd-catalyzed Suzuki coupling reaction.…”

“…Vascular endothelial growth factor (VEGF) and its receptors, especially VEGFR-2, are recognized as the major mediator of tumor angiogenesis. 2,3 Aberrant angiogenesis has been widely observed in many kinds of cancers including liver cancer and hepatic carcinoma. 4 Therefore, VEGFR-2 is a validated target for the discovery of novel anti-angiogenesis agents.…”