β-elemene enhances anticancer bone neoplasms efficacy of paclitaxel through regulation of GPR124 in bone neoplasms cells.

The purpose of the present study was to investigate the anticancer effects of β-elemene and paclitaxel for bone neoplasms. MTT assay, reverse transcription-quantitative polymerase chain reaction, western blotting, flow cytometry and immunostaining were used to analyze the combined effects of β-elemene and paclitaxel both in vitro and in vivo. The results demonstrated that combined treatment of β-elemene and paclitaxel (β-elemene-paclitaxel) significantly inhibited growth and aggressiveness of U-2OS cells compared with either β-elemene or paclitaxel treatment alone. It was demonstrated that β-elemene promoted paclitaxel-induced apoptosis of U-2OS cells. Anti-apoptosis B-cell lymphoma (Bcl)-2 and Bcl-w genes were downregulated and pro-apoptotic Bcl-2-associated agonist of cell death and caspase-3 genes were upregulated in U-2OS cells following treatment with β-elemene-paclitaxel. Treatment of β-elemene-paclitaxel arrested the cell cycle and decreased cyclin-dependent kinase, cyclin-B1, P21 and P27 expression levels and decreased resistant genes alterations of ATP binding cassette subfamily B member 1, LDL receptor related protein and TS in U-2OS cells. Results demonstrated that β-elemene-paclitaxel decreased G-protein coupled receptor 124 (GPR124), vascular endothelial growth factor receptor, matrix metallopeptidase (MMP)-3, MMP-9 expression levels and increased endostatin, TIMP metallopeptidase inhibitor (TIMP)-1, TIMP-2 expression in U-2OS cells. In vivo assay demonstrated that β-elemene-paclitaxel treatment inhibited tumor growth of BALB/c-nu/nu nude mice and prolonged survival rate of tumor-bearing mice. Immunostaining demonstrated that β-elemene-paclitaxel treatment increased apoptotic bodies, GPR124 and increased endostatin, TIMP-1 and TIMP-2 expression in tumor tissues. In conclusion, these results suggest that the combined treatment of β-elemene-paclitaxel is more effective at inhibiting bone neoplasm growth than β-elemene or paclitaxel single treatment GPR124.