In vitro and in vivo anti-tumor effect of Trichobakin fused with urokinase-type plasminogen activator ATF-TBK

• Published in: Molecular biology reports Vol. 51; no. 1; p. 130
• Main Authors: Pham, Dan Duc, Pham, Thi Hue, Bui, Thi Huyen, Britikova, Elena V., Britikov, Vladimir V., Bocharov, Eduard V., Usanov, Sergey A., Phan, Van Chi, Le, Thi Bich Thao
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01-12-2024; Springer Nature B.V
• Subjects: Adenocarcinoma; Animal Anatomy; Animal Biochemistry; Antitumor agents; Biomedical and Life Sciences; Cancer; Clinical trials; Drug delivery; Hematology; Hepatocellular carcinoma; Histology; Life Sciences; Lung carcinoma; Morphology; Original Article; Prostate carcinoma; Protein biosynthesis; Tumor cell lines; Tumors; U-Plasminogen activator; Urokinase plasminogen activator (uPA); Ribosome inactivating protein (RIP); Trichobakin (TBK); ATF-TBK; Cytotoxic activity
• ISSN: 0301-4851; 1573-4978
• DOI: 10.1007/s11033-023-09036-6

Background
Trichobakin (TBK), a member of type I ribosome-inactivating proteins (RIPs), was first successfully cloned from
Trichosanthes sp Bac Kan 8–98
in Vietnam. Previous study has shown that TBK acts as a potential protein synthesis inhibitor; however, the inhibition efficiency and specificity of TBK on cancer cells remain to be fully elucidated.
Methods and results
In this work, we employed TBK and TBK conjugated with a part of the amino-terminal fragment (ATF) of the urokinase-type plasminogen activator (uPA), which contains the Ω-loop that primarily interacts with urokinase-type plasminogen activator receptor, and can be a powerful carrier in the drug delivery to cancer cells. Four different human tumor cell lines and BALB/c mice bearing Lewis lung carcinoma cells (LLC) were used to evaluate the role of TBK and ATF-TBK in the inhibition of tumor growth. Here we showed that the obtained ligand fused RIP (ATF-TBK) reduced the growth of four human cancer cell lines in vitro in the uPA receptor level-dependent manner, including the breast adenocarcinoma MDA-MB 231 cells and MCF7 cells, the prostate carcinoma LNCaP cells and the hepatocellular carcinoma HepG2 cells. Furthermore, the conjugate showed anti-tumor activity and prolonged the survival time of tumor-bearing mice. The ATF-TBK also did not cause the death of mice with doses up to 48 mg/kg, and they were not significantly distinct on parameters of hematology and serum biochemistry between the control and experiment groups.
Conclusions
In conclusion, ATF-TBK reduced the growth of four different human tumor cell lines and inhibited lung tumor growth in a mouse model with little side effects. Hence, the ATF-TBK may be a target to consider as an anti-cancer agent for clinical trials.