Enhanced antitumor and anti-metastasis efficiency via combined treatment with CXCR4 antagonist and liposomal doxorubicin.

Metastasis is the main cause of cancer treatment failure and death. However, current therapies are designed to impair carcinoma metastasis mainly by impairing initial dissemination events. CXCR4 is a G-protein coupled receptor that exclusively binds its ligand CXCL12, which can stimulate cells to metastasize to distant sites. As the antagonist of chemokine receptor CXCR4, Peptide S exhibited anti-metastasis effect. In order to enhance treatment efficiency through destroying primary tumors and inhibiting their metastases, we combined PEGylated doxorubicin-loaded liposomes (DOX-Lip) with anti-metastasis Peptide S for tumor therapy for the first time. DOX-Lip exhibited similar cytotoxic activity compared to free DOX in vitro, and Peptide S showed no toxic effect on cell viability. However, the Peptide S sensitized CXCR4-positive B16F10 melanoma cells to DOX-Lip (5 μM) when cocultured with stromal cells (50.18±0.29% of viable cells in the absence of Peptide S vs 33.70±3.99% of viable cells in the presence of Peptide S). Both Peptide S and DOX-Lip inhibited the adhesion of B16F10 cells to stromal cells. We further confirmed that the inhibition of phosphorylated Akt (pAkt) by Peptide S played a key role due to the fact that activation of pAkt by DOX-Lip promoted resistance to chemotherapy. Migration and invasion assays showed that DOX-Lip enhanced anti-metastasis effect of Peptide S in vitro because of the cytotoxicity of doxorubicin. In vivo studies also showed that the combined treatment with DOX-Lip and Peptide S not only retarded primary tumor growth, but also reduced lung metastasis. Both the DOX-Lip and DOX-Lip+Peptide S exhibited even more outstanding tumor inhibition effect (with tumor growth inhibition rates of 32.1% and 37.9% respectively). In conclusion, our combined treatment with CXCR4 antagonist and liposomal doxorubicin was proved to be promising for antitumor and anti-metastasis therapy.