Anti-metastatic Efficacy of Traditional Chinese Medicine (TCM) Ginsenoside Conjugated to a VEFGR-3 Antibody on Human Gastric Cancer in an Orthotopic Mouse Model.
Background/Aim: The aim of the present study was to investigate the efficacy of a traditional Chinese medicine (TCM), VEGFR-3 antibody-conjugated ginsenoside Rg3nanoemulsion (VRIN), targeting lymphangiogenesis, on the inhibition of tumor growth and metastasis in an orthotopic mouse model of human gastric cancer. Materials and Methods: An orthotopic nude-mouse model of gastric cancer was established with the red fluorescent protein (RFP)-expressing human gastric cancer cell line NUGC-4-RFP. The tumor-bearing mice were treated with vehicle (0.2 ml normal saline every other day, iv), 5-FU (20 mg/kg once a week, i.p.) and VRIN (1 mg/kg every other day, i.v.). Real-time fluorescence imaging was performed to assess tumor inhibition in each group. Metastasis was evaluated by open fluorescence imaging at autopsy. The expression of lymphangiogenesis-related factors VEGF-C, VEDF-D and VEGFR-3 in the tumors were analyzed by immunohistochemistry and real-time RCP. Results: VRIN and 5-FU significantly inhibited primary tumor growth as compared to vehicle control (p<0.05). However, significant inhibition of lymph-node metastasis was only found in the VRIN-treated group (p<0.05). The expression of VEGF-C, VEGF-D and VEGFR-3 in the tumor was suppressed by VRIN treatment (p<0.05). Expression of VEGF-D and VEGFR-3 in the 5-FU-treated group was not significantly increased (p>0.05). No obvious toxicity was found in VRIN- and 5-FU-treated groups. Conclusion: Lymphangiogenesis-targeted ginsenoside Rg3immune-nanoemulsion inhibited tumor growth and reduced lymphatic metastasis by suppressing expression of VEGF-C, VEGF-D and VEGFR-3 in an orthotopic mouse model of human gastric cancer. Our study demonstrates the potential of TCM as an effective targeted treatment for metastatic gastric cancer.
Clinical Traditional Chinese Medical College, Yangzhou University, Yangzhou, P.R. China.|Affiliated Yangzhou Hospital of Nanjing University of Traditional Chinese Medicine, Yangzhou, P.R. China.|Yangzhou Traditional Chinese Medicine Hospital, Yangzhou, P.R. China.
Xiaojun
X
Dai
Clinical Traditional Chinese Medical College, Yangzhou University, Yangzhou, P.R. China.
Dongmei
D
Liu
Clinical Traditional Chinese Medical College, Yangzhou University, Yangzhou, P.R. China.
Moxiang
M
Liu
Yangzhou Traditional Chinese Medicine Hospital, Yangzhou, P.R. China.
Xiaochun
X
Zhang
Yixing People's Hospital, Yixing, P.R. China.
Weiming
W
Wang
Clinical Traditional Chinese Medical College, Yangzhou University, Yangzhou, P.R. China.
Feng
F
Jin
Clinical Traditional Chinese Medical College, Yangzhou University, Yangzhou, P.R. China.
Yayun
Y
Qian
Clinical Traditional Chinese Medical College, Yangzhou University, Yangzhou, P.R. China.
Xuanyi
X
Wang
Affiliated Yangzhou Hospital of Nanjing University of Traditional Chinese Medicine, Yangzhou, P.R. China.
Jingjing
J
Zhao
Yangzhou Traditional Chinese Medicine Hospital, Yangzhou, P.R. China.
Yongjian
Y
Wu
Affiliated Yangzhou Hospital of Nanjing University of Traditional Chinese Medicine, Yangzhou, P.R. China.
Fangfang
F
Xiong
Affiliated Yangzhou Hospital of Nanjing University of Traditional Chinese Medicine, Yangzhou, P.R. China.
N A
NA
Chang
Origin Biosciences Inc., Nanjing, P.R. China.
Y U
YU
Sun
AntiCancer, Inc., San Diego, CA, U.S.A.|Origin Biosciences Inc., Nanjing, P.R. China.
Zhijian
Z
Yang
AntiCancer, Inc., San Diego, CA, U.S.A. liuyq@yzu.edu.cn all@anticancer.com.|Department of Surgery, University of California, San Diego, CA, U.S.A.
Robert M
RM
Hoffman
Clinical Traditional Chinese Medical College, Yangzhou University, Yangzhou, P.R. China liuyq@yzu.edu.cn all@anticancer.com.
Yanqing
Y
Liu
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage* / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000737:chemistry; D036145:Ginsenosides / Q000008:administration & dosage*; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D042583:Lymphangiogenesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D058726:Nanoconjugates / Q000737:chemistry; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000276:immunology*; D000097573:Red Fluorescent Protein
D000906:Antibodies; D000970:Antineoplastic Agents; D004365:Drugs, Chinese Herbal; D005472:Fluorouracil; D036145:Ginsenosides; D008164:Luminescent Proteins; D058726:Nanoconjugates; D040321:Vascular Endothelial Growth Factor Receptor-3; D000097573:Red Fluorescent Protein; C581309:FLT4 protein, human
Ginsenoside Rg3; RFP; VEGFR-3; efficacy; gastric cancer; imaging; immune-nanoemulsion; metastasis; nude mice; orthotopic; red fluorescent protein