LY2109761 Potentiates 5-FU-Induced Cytotoxicity in HCT 116 Cells and Preserves PBMC Viability In Co-Culture Models

Colorectal cancer remains a leading cause of cancer-related mortality worldwide, with chemoresistance representing a major therapeutic challenge. The transforming growth factor-beta (TGF-β) signaling pathway contributes to tumor progression and treatment resistance, making it a promising target for combination therapy. This study investigated whether the dual TGF-β receptor I/II inhibitor LY2109761 enhances the cytotoxic effects of 5-fluorouracil (5-FU) in colorectal cancer cells while assessing its impact on immune cell viability. Cell viability was determined by MTT assay following treatment with 5-FU and LY2109761, alone or in combination, in HCT 116 colorectal cancer cells. Preliminary Bliss independence analysis indicated a localized positive interaction at selected concentrations; however, the limited concentration matrix precludes a definitive conclusion regarding pharmacological synergy. Exploratory ELISA analyses revealed non-significant changes in TGF-β and TGF-βR2 levels following treatment. Because downstream TGF-β signaling was not directly assessed, these findings should not be interpreted as mechanistic evidence of pathway inhibition. Nevertheless, LY2109761 enhanced the cytotoxic activity of 5-FU under selected concentration conditions and did not markedly increase apoptotic death in PBMCs, supporting further mechanistic and preclinical investigation of this proof-of-concept combination strategy.