The Anti-Tubercular Aminolipopeptide Trichoderin A Displays Selective Toxicity against Human Pancreatic Ductal Adenocarcinoma Cells Cultured under Glucose Starvation

Abstract

Pancreatic ductal adenocarcinoma remains a highly debilitating condition with no effective disease-modifying interventions. In our search for natural products with promising anticancer activity, we identified the aminolipopeptide trichoderin A as a potential candidate. While it was initially isolated as an antitubercular peptide, we provide evidence that it is also selectively toxic against BxPC-3 and PANC-1 human pancreatic ductal adenocarcinoma cells cultured under glucose deprivation. This has critical implications for the pancreatic ductal adenocarcinoma, which is characterized by nutrient deprivation due to its hypovascularized network. We have also successfully simplified the trichoderin A peptide backbone, allowing greater accessibility to the peptide for further biological testing. In addition, we also conducted a preliminary investigation into the role of peptide lipidation at the N-terminus. This showed that analogues with longer fatty acyl chains exhibited superior cytotoxicity than those with shorter acyl chains. Further structural optimization of trichoderin A is anticipated to improve its biological activity, whilst ongoing mechanistic studies to elucidate its intracellular mechanism of action are conducted in parallel.