Inhibition of MMP‐9 transcription and suppression of tumor metastasis by pyrrole‐imidazole polyamide

(Cancer Sci 2010; 101: 759–766)Matrix metalloproteinase (MMP)‐9, the 92‐kDa type IV collagenase, contributes to tumor invasion and metastases, and strategies to down‐regulate its expression could ultimately be of clinical utility. A pyrrole‐imidazole (PI) polyamide that targets the activator protein‐1 (AP‐1)‐binding site of the MMP‐9 promoter was designed and synthesized as a gene‐silencing agent for tumor metastases. The synthesized product showed selective DNA binding ability. The MMP‐9 PI polyamide significantly inhibited MMP‐9’s mRNA expression, protein level, and enzymatic activity in human breast adenocarcinoma cells (MDA‐MB‐231). Furthermore, the MMP‐9 PI polyamide inhibited migration and invasion by in vitro wound‐healing and matrigel‐invasion assay. The FITC‐labeled PI polyamide was localized in nuclei in 45 min of incubation with an MDA‐MB‐231 cell and remained in the nuclei for up to 96 h after incubation in vitro. It was also quickly localized in the mouse cellular nuclei of many tissues, including liver, kidney, and spleen, after intravenous injection without using any drug‐delivery system. Moreover, the polyamide treatment significantly decreased metastasis in a mouse model of liver metastasis. Our results suggest that this PI polyamide, which targets the MMP‐9 gene promoter, can be a novel MMP‐9 down‐regulating molecule for antimetastasis.