Efficacy and Mechanism of Action of a Novel Class of Antic-Cancer Drugs

Abstract

The incidence of cancer worldwide has increased over the years, and gastrointestinal cancers (G.I.) are amongst the most common forms of cancer. Nevertheless, there is still no curative treatments for this group of tumors. Nucleoside analogues are widely used in cancer treatment. The prevailing compounds are Gemcitabine (used for pancreatic cancer and other carcinomas), 5-Fluorouracil (used in breast, colon, and other cancers), Cytarabine and Clofarabine (used in leukemias). Gemcitabine, the current standard of care for various forms of solid tumors, has a limited efficacy against pancreatic cancer. The objective of this project was the development of effective drugs against pancreatic cancer. We focused on a novel class of nucleoside analogues designed to bypass the most common cellular road blocks and resistance mechanisms. After an extensive screen for cell killing activity, two lead molecules were exclusively studied: LCB2151 and LCB2132. These two molecules showed high efficacy in killing human cancer cells from three different human G.I. cell lines: BxPC3 and Capan-2, two pancreatic cell lines representative of K-Ras positive and negative tumors, as well as the liver cell line HepG2. LCB2151 showed high efficacy in killing Gemcitabine-resistant cancer cells, and a low toxicity in normal cells. Interestingly, results show that these prodrugs can efficiently bypass key resistance mechanisms developed by cancer cells. The results obtained in this project are promising and could pave the way for a more effective treatment of pancreatic cancer.