The Mechanism of Action of a New Class of Nucleoside Analogs Targeting Gastrointestinal Tumours

Abstract

Gastrointestinal malignancies such as liver and pancreatic cancers are the deadliest due to late detection and drug resistance. Nucleoside analogues, like Gemcitabine, are the conventional therapy despite their little impact on survival and off-target toxicity. A novel class of nucleoside analogues able to evade drug resistance mechanisms has been developed by the Guindon group and biologically screened in our lab. Some of these proprietary molecules were further equipped with a lipoate moiety designed to target cancer cell metabolism. LCB2151 and LCB2179 have emerged as the lead molecules in this class, with an IC50 of 10-15 µM in the Gemcitabine-resistant human pancreatic (Capan-2 & Panc-1) cancer cell lines. The focus of this project is deciphering the cellular mechanisms activated by LCB2151 in these pancreatic cancer lines. A series of biased molecular approaches, like gene expression profiling, and unbiased large throughput proteomic and metabolomics analyses were applied to identify potential targets and affected pathways. Results collectively show that LCB2151 evades drug resistance mechanisms, increases pro-apoptotic markers and impairs mitochondrial respiration as early as 6 hours posttreatment. Furthermore, MS/MS analyses reveal that LCB2151 alters the levels of several metabolites in the central carbon metabolism pathway and identifies the citric acid cycle enzyme α-ketoglutarate dehydrogenase as a potential molecular target of LCB2151. Understanding the exact mechanism of action of our lead molecule along with extensive testing on murine cancer models, will surely pave its way to clinical testing and evaluation.