Abstract

Pancreatic cancer is an aggressive neoplasm, with a mortality rate close to 100%. Currently, the most successful agent for pancreatic cancer treatment is gemcitabine, although the overall effect in terms of patient survival remains very poor. This study was initiated to evaluate a novel class of anti-cancer agents against pancreatic cancer. This group of compounds belongs to the dipyridyl thiosemicarbazone (DpT) class that have been shown to have potent and selective activity against a range of different neoplasms in vitro and in vivo (Whitnall M., Howard J., Ponka P. and Richardson D.R. 2006, PNAS 40:14901-6). We demonstrate for the first time in pancreatic cancer that these agents increase the expression of the growth and metastasis suppressor, N-myc down-stream regulated gene 1 (NDRG1), and also its phosphorylation at Ser-330 and Thr-346 that is important for its activity against this tumor. In addition, these agents increased expression of the cyclin-dependent kinase inhibitor p21^CIP1/WAF1, while decreasing cyclin D1 in pancreatic cancer cells. Together, these molecular alterations account, in part, for the pronounced anti-tumor activity observed. Indeed, these agents had significantly higher anti-proliferative activity in vitro than the established treatments for pancreatic cancer, namely gemcitabine and 5-fluorouracil. Studies in vivo demonstrated that a novel thiosemicarbazone, namely di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone hydrochloride (DpC), completely inhibited the growth of pancreatic cancer xenografts with no evidence of marked alterations in normal tissue histology. Collectively, our studies have identified molecular effectors of a novel and potent anti-tumor agent that could be useful for pancreatic cancer treatment.