Down-Regulation of the Mammalian Target of Rapamycin (mTOR) Pathway Mediates the Effects of the Paeonol-Platinum(II) Complex in Human Thyroid Carcinoma Cells and Mouse SW1736 Tumor Xenografts.

Abstract

BackgroundThis study aimed to investigate the effects of the paeonol-platinum(II) (PL-Pt[II]) complex on SW1736 human anaplastic thyroid carcinoma cell line and the BHP7-13 human thyroid papillary carcinoma cell line in vitro and on mouse SW1736 tumor xenografts in vivo.Material/MethodsThe cytotoxic effects of the PL-Pt(II) complex on SW1736 cells and BHP7-13 cells was measured using the MTT assay. Western blot measured the expression levels of cyclins, cell apoptotic proteins, and signaling proteins. DNA content and apoptosis were detected by flow cytometry. SW1736 cell thyroid tumor xenografts were established in mice followed by treatment with the PL-Pt(II) complex.ResultsTreatment of the SW1736 and BHP7-13 cells with the PL-Pt(II) complex reduced cell proliferation in a dose-dependent manner, with an IC50 of 1.25 μM and 1.0 μM, respectively, and increased the cell fraction in G0/G1phase, inhibited p53, cyclin D1, promoted p27 and p21 expression, and significantly increased the sub-G1 fraction. Treatment with the PL-Pt(II) complex increased caspase-3 degradation, reduced the expression of p-4EBP1, p-4E-BP1 and p-S6, and reduced the expression of p-ERK1/2 and p-AKT. Treatment with the PL-Pt(II) complex reduced the volume of the SW1736 mouse tumor xenografts on day 14 and day 21, and reduced AKT phosphorylation and S6 protein expression and increased degradation of caspase-3.ConclusionsThe cytotoxic effects of the PL-Pt(II) complex in human thyroid carcinoma cells, including activation of apoptosis and an increased sub-G1 cell fraction of the cell cycle, were mediated by down-regulation of the mTOR pathway.