title: Enhanced antitumor and anti-metastasis efficiency via combined treatment with CXCR4 antagonist and liposomal doxorubicin.
abstract: 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.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: Mei
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
authors.forename: Yayuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
authors.forename: Qianyu
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
authors.forename: Huile
authors.initials: H
authors.lastname: Gao
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China. Electronic address: qinhe@scu.edu.cn.
authors.forename: Qin
authors.initials: Q
authors.lastname: He
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008081:Liposomes; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D008081:Liposomes; D019718:Receptors, CXCR4; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D051058:Oncogene Protein v-akt; D002118:Calcium
keywords: CXCR4 antagonist; Combined treatment; Liposomal doxorubicin; Metastasis