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Multitargeting Strategy Using Tetrathiomolybdate and Lenvatinib: Maximizing Antiangiogenesis Activity in a
Li Nan1, Wan Yuan2, Chen Guodong1
1Department of Interventional Radiology, Guangzhou First People's Hospital, The Second Affiliated Hospital of South China University of Technology, Guangzhou 510180, China.
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.
Insights
Copper chelator ammonium tetrathiomolybdate (TM) combined with lenvatinib significantly suppresses hepatocellular carcinoma growth by reducing tumor angiogenesis. This combination therapy shows promise for clinical application in treating liver cancer.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Copper plays a role in tumor progression.
- Hepatocellular carcinoma (HCC) is a significant global health concern.
- Anti-angiogenesis therapies are crucial in cancer treatment.
Purpose of the Study:
- To investigate the anti-tumor effects of ammonium tetrathiomolybdate (TM), a copper chelator, in combination with lenvatinib.
- To evaluate the multi-anti-angiogenesis activity of this combination therapy in hepatocellular carcinoma.
- To determine the impact on tumor growth, vascular endothelial growth factor (VEGF), and microvessel density (MVD).
Main Methods:
- Hepa1-6 hepatoma cells were implanted in C57 mice.
- Mice were randomized into five groups: TM, Lenvatinib, TM+Lenvatinib, Control, and Copper (II) Gluconate.
- Tumor weight, volume, serum/intratumoral copper levels, VEGF expression, and MVD were analyzed post-treatment.
Main Results:
- Copper concentrations correlated positively with tumor load.
- The combination of TM and lenvatinib significantly reduced tumor weight and volume compared to controls.
- Combined therapy led to decreased VEGF expression and MVD, indicating reduced angiogenesis.
Conclusions:
- Copper promotes tumor progression; copper chelation suppresses tumor growth.
- The combination of TM and lenvatinib exhibits potent anti-angiogenesis activity against HCC.
- This combination therapy offers a promising strategy for hepatocellular carcinoma treatment.
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