Human tongue carcinoma growth is inhibited by selective antigelatinolytic peptides

Matrix metalloproteinases (MMP-2 and MMP-9, or gelatinases) are involved in tongue SCC invasion, metastasis and angiogenesis. We have recently shown that a novel and selective hydrophobic cyclic CTTHWGFTLC (CTT1) peptide is inhibitor for MMP-2 and MMP-9 (Koivunen et al., Nat Biotechnol 1999; 17:768-74). In this study, we demonstrate that both the new hydrophilic derivate GRENYHGCTTHWGFTLC (CTT2) peptide and the CTT1 peptide inhibited specifically the human tongue squamous cell carcinoma (HSC-3) cell-derived gelatinolytic activity and in vitro invasion and migration of these cells (p < or = 0.049). In situ zymography revealed that both peptides also inhibited clearly almost all of the gelatinolytic activity present in the human tongue SCC tissue sections, indicating that MMP-2 and MMP-9 are the major gelatinases detected in the tongue carcinomas. However, CTT2 did not inhibit the type I collagen degradation by human collagenases (MMP-1, MMP-8 and MMP-13). Furthermore, CTT2 reduced the blood vessel density (p < or = 0.043) and clearly improved the survival of the mice bearing human tongue carcinoma xenografts (p < or = 0.012). Overall, we suggest that CTT1 and CTT2 peptides being selective gelatinase inhibitors with significant anti-tumor properties could be useful to diminish the invasion and angiogenesis of human tongue carcinomas characterized by enhanced gelatinolytic activity in tumors.