Title:Multitargeting Strategy Using Tetrathiomolybdate and Lenvatinib: Maximizing Antiangiogenesis
Activity in a Preclinical Liver Cancer Model
Volume: 23
Issue: 7
Author(s): Li Nan*, Wan Yuan, Chen Guodong and Huang Yonghui*
Affiliation:
- Department of Interventional Radiology, Guangzhou First People’s Hospital, The Second Affiliated Hospital of South China University
of Technology, Guangzhou 510180, China
- Department of Interventional Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou,
Guangdong 510080, China
Keywords:
Liver tumor, copper, copper chelator, lenvatinib, combination therapy, angiogenesis.
Abstract:
Purpose: The study aims to investigate the suppressing tumor-promoting effects via multi-anti-angiogenesis
activity of the copper chelator (ammonium tetrathiomolybdate, TM) combined with lenvatinib for hepatocellular carcinoma.
Methods: A total of 55 C57 mice were injected subcutaneously with Hepa1-6 hepatoma cell suspensions into the right
posterior thigh. After 7 days, the subcutaneous tumors were formed, and the mice were randomly divided into five
groups: TM (G1), Lenvatinib (G2), TM+Lenvatinib (G3), Control (G4), and Copper (II) Gluconate (G5). The copper
concentrations in serum and tumors were measured at the predetermined time points. After 14 days of treatments,
tumor weight and volumes were analyzed, histology was observed, and the expressions of vascular endothelial growth
factor (VEGF) and microvessel density (MVD) in tumor tissues were measured by immunohistochemistry.
Results: The median concentration of copper in serum was 401.70, 469.40, and 665.35 μg/L in normal mice, in mice 7
days after implantation, and in the control group, respectively. The intratumoral copper concentrations were higher in
G4 mice than in mice 7 days after implantation (P < 0.05). The serum concentration of copper was higher in G5 than
all the other groups (P < 0.05; (G1, G2, and G3) vs. G4, P < 0.05; G1 vs. G2, P = 0.013; G2 vs. G3, P = 0.018; G1 vs.
G3, P = 0.903. The intratumoral copper concentrations were 608.40, 980.00, 539.31, and 2938.90 μg/L in G1, G2, G3,
and G5, respectively. The average tumor weight was 0.55, 0.44, 0.08, 1.37, and 3.11 in G1, G2, G3, G4, and G5, respectively.
G5 vs. other groups, P < 0.05; (G1, G2, and G3) vs. G4, P < 0.05; G1 vs. G3, P < 0.05; G2 vs. G3, P < 0.05;
G1 vs. G2, P > 0.05. Furthermore, the expression levels of VEGF were significantly lower in G1, G2, and G3 than in
G4 and G5 (P < 0.05). A similar trend was observed for MVD in the five groups, but no significant difference was
detected in G1 and G2.
Conclusion: The study showed a significant positive correlation between tumor load and copper. Copper promotes
tumor progression, but copper chelating suppresses tumor growth. The combination of TM with lenvatinib reduces
tumor angiogenesis and improves the effect of antitumor treatment. These findings underlie the clinical application of
combination therapy.
