Anti-tumor Effect of the Adamantyl Retinoid ST1926 in Combination with 5-Fluorouracil in Pancreatic Cancer

Abstract

Pancreatic cancer is considered as one of the most fatal malignancies, ranking as the seventh leading cause of worldwide cancer-related deaths in industrialized countries and the third most common in the U.S.A. Despite recent advances in surgical techniques, chemotherapy and radiation therapy, the five year’s survival rate has not significantly improved, confirming the need for novel therapeutics strategy. Retinoid related molecules are crucial potential agents for cancer treatment. One of them is ST1926, a synthetic adamantyl retinoid that has shown potent anti-tumor effect in many models of human cancer. As the molecular pathogenesis of pancreatic cancer is very complex and the development and metastasis related to the abnormality of various gene mutations and cell signaling pathways, then combining several drugs that target different signaling pathways provide a research hot spot. Therefore, we aimed to investigate the anti-tumor activities of ST1926 alone and in combination with 5-fluorouracil (5-FU) in pancreatic cancer in in vitro models. We used human pancreatic cancerous cell lines (Panc-1 and Capan-1) that harbor different genetic mutations. We showed that ST1926 in combination with 5-FU were significantly more effective in inhibiting pancreatic cancer cell lines proliferation than either cytotoxic agent alone. Furthermore, ST1926/5-FU induced apoptosis as evidenced by PARP cleavage and mitochondrial membrane potential dissipation. In addition, ST1926/5-FU increased the protein levels of total p53 and γH2AX while decreasing that of DNA polymerase α (POLA-1). In conclusion, our study supports the possibility that the combined treatment of ST1926 and 5-FU may be potentially effective and a critical strategy for pancreatic cancer treatment.