ADH-1 suppresses N-cadherin-dependent pancreatic cancer progression Free

LB-261

Pancreatic cancer is one of the most aggressive malignant diseases. We recently reported that N-cadherin plays a key role in tumor progression and metastasis in pancreatic cancer. In addition, recent studies have indicated that synthetic short cyclic peptides containing the sequence, His-Ala-Val (HAV), which is found in the first extracellular (EC1) domains of all classical cadherins, can inhibit N-cadherin function. These data led us to ask whether blocking N-cadherin function would prevent the malignant behavior of N-cadherin expressing pancreatic cancer cells. Our hypothesis for the current study was that peptides would prevent tumor growth and metastasis of N-cadherin over-expressing pancreatic cancer cells. The cyclic peptides used in this study, ADH-11 (N-Ac-CHGVDC-NH₂) and ADH-1 (N-Ac-CHAVC-NH₂) were kindly provided by Adherex Technologies Inc. ADH-1 was previously reported to inhibit N-cadherin mediated cell adhesion, whereas ADH-11 had no effect on N-cadherin mediated cell-cell interactions and was used as a control peptide. Experimental Design: The effect of ADH-1 on N-cadherin-mediated cell scattering and migration in response to collagen I was examined using pancreatic cancer cells (BxPC-3 and Capan-1). We also examined the influence of ADH-1 on cell proliferation and apoptosis. Furthermore, in vivo animal studies were performed using orthotopic injection of N-cadherin over-expressing BxPC-3 cells with or without ADH-1 treatment. Results: BxPC-3 and Capan-1 cells showed increased expression of N-cadherin in response to collagen I. This increase in N-cadherin promoted cell scattering and migration in response to collagen I. ADH-1 prevented these changes, but did not inhibit up-regulation of N-cadherin. TUNEL assays showed that ADH-1 induced apoptosis in a concentration dependent and N-cadherin dependent manner. We recently reported that pancreatic cancer cells knocked down for N-cadherin formed significantly smaller tumors as compared to N-cadherin over-expressing cells using an orthotopic mouse model for pancreatic cancer. Histological examination demonstrated micro-metastases in the lungs of mice bearing tumors comprised of N-cadherin over-expressing cells, whereas no lung metastases were observed in mice bearing tumors comprised of N-cadherin knockdown cells. In agreement with these data, blocking N-cadherin function by ADH-1 treatment resulted in significant reductions in tumor growth and lung metastasis in a mouse model for pancreatic cancer. Conclusions: The N-cadherin antagonist, ADH-1, has significant anti-tumor activity against N-cadherin-expressing cells using in vitro assays and in an orthotopic mouse model for pancreatic cancer, raising the possibility that N-cadherin antagonists have therapeutic potential for the treatment of pancreatic cancer in humans.