Galloyl cyclic-imide derivative CH1104I inhibits tumor invasion via suppressing matrix metalloproteinase activity
Matrix metalloproteinase-2 (MMP-2) and MMP-9 have been associated with the ability of tumor cells to metastasize due to their capacity to degrade type IV collagen, the main component of basement membrane, and to their elevated expression in malignant tumors. (S)-methyl 6-(benzyloxycarbonylamino)-2-(2-(S)-2,6-dioxo-3-(3,4,5-trimethoxybenzamido) piperidin-1-yl)acetamido)hexanoate (CH1104I) is a galloyl cyclic-imide derivative designed to fit and extend into the S1' active pocket of MMP-2 and MMP-9. We aimed to evaluate the efficacy of CH1104I as a candidate compound for anti-invasion and anti-metastasis of tumor cells. CH1104I significantly blocked gelatinase activity as evidenced by a decrease in the degradation of succinylated gelatin. Gelatin zymography analysis showed that the compound (7-210 μM) inhibited the activity of MMP-2 and MMP-9 produced by human ovarian carcinoma SKOV3 cells. Inhibition of MMP-2 and MMP-9 expression was also observed using the assays of immunocytochemical staining and Western blot analysis. The results showed that CH1104I suppressed the expression of zymogens and active-MMP-2 and MMP-9. The effects of CH1104I on invasion and migration of SKOV3 cells were then measured. CH1104I displayed an inhibitory effect on the penetration of SKOV3 cells through Matrigel-coated membrane in transwell chamber. Furthermore, Lewis lung carcinoma (LLC) model was employed to evaluate the efficacy of CH1104I in vivo. A significant inhibition of pulmonary metastasis of carcinoma cells was observed in CH1104I-administrated mice (25-100 mg/kg). These results suggest that CH1104I is a potential MMP-2 and MMP-9 inhibitor that may effectively suppress tumor invasion and metastasis.