ATIQCTPC targeting MMP-9: a key step to slowing primary tumor growth and inhibiting metastasis of lewis lung carcinoma in vivo
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Yuji Wang1, Xinyi Xu1, Ce Song3, Jianhui Wu1, Xi Hu1, Haimei Zhu1, Xiaoyi Zhang1, Yaonan Wang1, Lin Gui1, Ming Zhao1,2 and Shiqi Peng1
1Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, China
2Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
3Ruikang Hospital, Guangxi University of Chinese Medicine, Nanning, China
Shiqi Peng, email: [email protected]
Ming Zhao, email: [email protected]
Ce Song, email: [email protected]
Keywords: MMP-9, tumor, metastasis, inflammation, TNF-α
Received: February 02, 2017 Accepted: June 02, 2017 Published: July 10, 2017
In this study we docked (6S)-3-acetyl-4-oxo-N-(2-(3,4,5,6-zetrahydroxytetrahydro-2H-pyran-2-carboxamido)ethyl)-4,6,7,12-tetrahydroindolo[2,3-a]quinolizine-6-carbo-xamide (ATIQCTPC) towards the active site of MMP-9, and showed that ATIQCTPC was able to effectively decrease the level of MMP-9 in the serum and the primary tumor of Lewis lung carcinoma (LLC) implanted C57BL/6 mice. As a MMP-9 inhibitor, ATIQCTPC inhibited the metastasis of LLC, and slowed the growth of the primary tumor of LLC implanted C57BL/6 in mice. The activities of ATIQCTPC to inhibit the ear edema and to decrease the serum levels of TNF-Î± and IL-8 of the mice treated with xylene were explored. The minimal effective dose of ATIQCTPC that can inhibit the primary tumour growth, prevent the metastasis of LLC and reduce the inflammatory response was 0.01 Î¼mol/kg. The minimal effective dose of ATIQCTPC inhibiting tumour growth and metastasis was 100-fold lower than that of (S)-3-acetyl- 4-oxo-4,6,7,12-tetrahydroindolo[2,3-a]quinolizine-6-carboxylic acid (ATIQC, parent compound). The minimal effective dose of ATIQCTPC inhibiting inflammation was 110-fold lower than that of aspirin. These superiorities reflected the rationality of ATIQCTPC design. The safety of the therapy was explained by 1 Î¼mol/kg of ATIQCTPC did not injure the kidney, the liver and the heart of the treated inflammation mice.
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