A recombinant peptide, hirudin, potentiates the inhibitory effects of stealthy liposomal vinblastine on the growth and metastasis of melanoma.
The metastasis of tumor cells is one of the major obstacles to successful clinical therapy. A treatment strategy by incorporating a specific inhibitor of thrombin, recombinant hirudin with stealthy liposomal vinblastine, was used in this study for inhibiting the metastasis of tumor cells and enhancing the efficacy of anti-tumor agents. In vitro cytotoxicity, cell adhesion to extracellular matrix (ECM) proteins, and cell invasion and migration assays were performed on human A375 melanoma cell line. In vivo measurement of coagulation parameters, inhibition of tumor growth, and inhibition of metastasis were assessed in female BALB/c mice. In vitro, vinblastine or stealthy liposomal vinblastine alone was effective to inhibit the growth of A375 cells. On the contrary, hirudin had no influence on either cytotoxicity when treating with hirudin alone or hirudin plus vinblastine. In addition, in vitro results showed that hirudin had no impact on the adhesion of tumor cells to extracellular matrix proteins, and metastasis and invasion of tumor cells. In mice, hirudin significantly inhibited the activity of thrombin. Furthermore, administered at the initial implantation of murine B16 melanoma cells, hirudin evidently delayed the growth of tumor, and depressed the occurrence of experimental lung metastasis. A subsequent administration of stealthy liposomal vinblastine resulted in further inhibiting growth and metastasis of tumor, indicating that hirudin plus stealthy liposomal vinblastine exhibited a significant anti-metastasis effect and slightly potent effect against tumor growth as compared with stealthy liposomal vinblastine alone. In conclusion, administration of recombinant hirudin followed by giving stealthy liposomal vinblastine may be beneficial for inhibiting the growth and metastasis of melanoma in vivo. The likely mechanism could be associated with inhibition of thrombin after administration of hirudin.
Guo
Rong-Rong
RR
State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
Liu
Yang
Y
Lu
Wan-Liang
WL
Zhao
Ji-Hui
JH
Wang
Xue-Qing
XQ
Zhang
Hua
H
Wang
Jian-Cheng
JC
Zhang
Xuan
X
Zhang
Qiang
Q
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004337:Drug Carriers; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D016326:Extracellular Matrix Proteins / Q000737:chemistry; D006629:Hirudins / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008081:Liposomes; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009362:Neoplasm Metastasis / Q000517:prevention & control; D010316:Particle Size; D011480:Protease Inhibitors / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013778:Tetrazolium Salts; D013844:Thiazoles; D014747:Vinblastine / Q000008:administration & dosage / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D016326:Extracellular Matrix Proteins; D006629:Hirudins; D008081:Liposomes; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D014747:Vinblastine; C022616:thiazolyl blue