Proscillaridin A Sensitizes Human Colon Cancer Cells to TRAIL-Induced Cell Death

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytotoxic cytokine that induces cancer cell death by binding to TRAIL receptors. Because of its selective cytotoxicity toward cancer cells, TRAIL therapeutics, such as recombinant TRAIL and agonistic antibodies targeting TRAIL receptors, have garnered attention as promising cancer treatment agents. However, many cancer cells acquire resistance to TRAIL-induced cell death. To overcome this issue, we searched for agents to sensitize cancer cells to TRAIL-induced cell death by screening a small-molecule chemical library consisting of diverse compounds. We identified a cardiac glycoside, proscillaridin A, as the most effective TRAIL sensitizer in colon cancer cells. Proscillaridin A synergistically enhanced TRAIL-induced cell death in TRAIL-sensitive and -resistant colon cancer cells. Additionally, proscillaridin A enhanced cell death in cells treated with TRAIL and TRAIL sensitizer, the second mitochondria-derived activator of caspase mimetic. Proscillaridin A upregulated TRAIL receptor expression, while downregulating the levels of the anti-cell death molecules, cellular FADD-like IL-1β converting enzyme-like inhibitor protein and Mcl1, in a cell type-dependent manner. Furthermore, proscillaridin A enhanced TRAIL-induced cell death partly via O-glycosylation. Taken together, our findings suggest that proscillaridin A is a promising agent that enhances the anti-cancer efficacy of TRAIL therapeutics.

Effect of oligosaccharyl transglycosylation on the cytotoxicity of cardiac glycoside proscillaridin A and its ability to inhibit hepatitis B virus infection

“…Therefore, this system enables the rapid investigation of glycosides that can exhibit more functions or glycan structures that can give new functions to glycosides. For instance, it has been reported that proscillaridin A promotes cell death by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) via O-glycosylation 33 . It may be possible to enhance the anticancer effects of TRAIL therapeutics and increase their speci city for cancer cells by modifying the glycan structure.…”