Investigating farnesene: A novel Cx43 inhibitor

Abstract

Understanding how cells communicate opens the door to new medical therapies. Connexin 43 (Cx43) is detected in most human cell types including cardiac tissue and certain tumours cells. Those cells communicate through gap junctions made by Cx43. Limited signalling between cells can lead to heart diseases. Terpenes and Terpenoids, synthesized via the mevalonate pathway through the condensation of isoprene units, are renowned for their broad biological activities, encompassing anti-cancer, anti-inflammatory, and cardio-protective effects [1]. Recent work by Mickus and colleagues in 2021 has confirmed Terpene’s direct effect on the conductivity of gap junctions [2]. This research aims to extend these findings by characterizing the influence of selected Terpenes on Cx43 gap junctions, evaluating their role as either inhibitors or activators in a pharmacological context. The methodology encompasses experimental studies on Novikoff-hepatoma cells originally obtained from a rat liver. This cell line is endogenously expressing Cx43, maintained in the LSMU, Institute of Cardiology, Laboratory of Cell Culture. Farnesene is an acyclic sesquiterpene from the Terpenes family selected for investigation. Itwas chosen based on its documented biological activities with a particular focus on showing the impact that Farnesene has on gap junction’s conduction. Additionally, there was an interest in exploring the Terpene’s linear structure and examining how its biological activity correlates with the length of the chain. We investigated the effect of Farnesene on the Cx43 gap junction’s conductivity, exploring its potential as a chemical modulator. This study aims to disclose the specific ways Farnesene influences Cx43 gap junctions, broadening our understanding of its role in intercellular communication. By assessing how Farnesene adjusts Cx43's activity, and determining its IC50 values and Hill coefficients we highlight its therapeutic promise for treating Cx43-linked conditions, such as cardiac arrhythmias and other pathologies associated with Cx43 dysregulation. We also carried out molecular docking of Farnesene into Cx43. This research is a step towards understanding how nature's bounty can be harnessed for our health, emphasizing the need for further exploration into the biological effects of natural compounds.