ATIQCTPC targeting MMP-9: a key step to slowing primary tumor growth and inhibiting metastasis of lewis lung carcinoma in vivo.

Yuji Wang,Xi Hu,Jianhui Wu,Lin Gui,Xinyi Xu,Haimei Zhu,Ce Song,Xiaoyi Zhang,Ming Zhao,Shiqi Peng,Yaonan Wang

doi:10.18632/oncotarget.19172

Abstract

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.

Highlights

The investigations of matrix metalloproteinase-9 (MMP-9) have attracted the interests of a series of fields
The migration number of A549 and Lewis lung carcinoma (LLC) cells treated with 0.2 μM ATIQCTPC is significantly lower than that of A549 and LLC cells treated with phosphatebuffered saline (PBS), and equals to that of A549 and LLC cells treated with 20 μM ATIQC
The invasion number of A549 and LLC cells treated with 0.2 μM ATIQCTPC is significantly lower than that of A549 and LLC cells treated with PBS, and equals to that of A549 and LLC cells treat by 20 μM ATIQC

Summary

Introduction

The investigations of matrix metalloproteinase-9 (MMP-9) have attracted the interests of a series of fields. To prevent the cancer patients from metastatic death, a series of MMP9 inhibitors such as bioactive polyphenols of green tea [8, 9], naturally occurred products [10,11,12], clinical drugs [13,14,15,16], and the synthetic compounds [17,18,19,20] were reported. Since most of these inhibitors received in vitro evaluation only, the in vivo active inhibitors are urgently needed.

Methods

Results

Conclusion