A novel chiral oxazoline copper(ii)-based complex inhibits ovarian cancer growth in vitro and in vivo by regulating VEGF/VEGFR2 downstream signaling pathways and apoptosis factors

Abstract

A novel chiral oxazoline copper(II)-based complex {[Cu(C₁₃H₁₄NO₃S)₂]}₂ (Cu-A) was synthesized by an in situ reaction using L-methioninol, 4-hydroxyisophthalaldehyde, sodium hydroxide and copper(II) nitrate trihydrate as reactants. Its crystal structure was characterized. In vitro, Cu-A was superior to cis-dichlorodiammineplatinum (DDP) in cytotoxicity and angiogenesis inhibition. Cu-A significantly induced apoptosis of ovarian cancer cells (SKOV3) and human umbilical vein endothelial cells (HUVECs), showing significant anti-ovarian cancer and anti-angiogenesis effects. Notably, Cu-A significantly inhibits the growth of ovarian cancer in nude mice xenografted with SKOV3 cells, and it is less renal toxic than DDP. The molecular mechanism of anti-ovarian cancer and anti-angiogenesis is possibly that it down-regulates the expression of the proteins ERK1/2, AKT, FAK, and VEGFR2 and their phosphorylated proteins p-ERK1/2, p-AKT, p-FAK, and p-VEGFR2 in the VEGF/VEGFR2 signal transduction pathway to inhibit SKOV3 cell and HUVEC proliferation, induce apoptosis, suppress migration and metastasis, and inhibit angiogenesis. What's more, Cu-A significantly inhibits ovarian tumor growth in vivo by inhibiting tumor cells from inducing vascular endothelial cells to form their own vasculature and by inhibiting the expression of the anti-apoptotic protein Bcl-2 and up-regulating the expression of the pro-apoptotic proteins Caspase-9 and Bax to induce apoptosis of tumor cells.