Anti-breast cancer activity of bioactive metabolites from Andrographis paniculata through inhibition of PI3K activity in triple negative breast cancer (MDA-MB-231) cells

Abstract

Andrographis paniculata, known for many therapeutic potentials such as antiviral, anti-microbial, anticancer, antineoplastic and anti-inflammation properties. Flavonoids and diterpenoids of A. paniculate were extensively studied for their anticancer and anti-inflammation properties. Although, extract of Andrographis paniculata have shown for exhibit anti-breast cancer activities, the molecular targets for the medicinal molecules of Andrographis paniculata are not yet reported. This research study is aimed to identify the anti-breast cancer molecules of Andrographis paniculata and to study the underlying mechanisms. In order to identify the active anticancer molecules that are responsible for we used in silico screening and docking studies. The in silico studies correlated with in vitro mechanistic studies to identify the target and their underlining mechanism of action. In this work, we have reported the bioactive compounds of Andrographis paniculata against PI3K using in vitro and molecular docking with in silico ADME studies. Based on their binding affinities to PI3K, the diterpenoid neoandrographolide suggested the excellent binding scores with PI3K in comparison with the reference inhibitor alepsilib. Furthermore, among them two molecules - andrographolide and neoandrographolide has suggested to have high absorption capacity in gastro-intestinal (GI) tract. In vitro validation results of these molecules against PI3K expressing MDA MB-231 cells have showed the neoandrographolide exhibited excellent anticancer effects against the MDA MB-231 cells. Further mechanistic studies have showed the inducting the programmed cell death and arrested the cancer cell proliferation in G-1 phase upon treatment with neoandrographolide in MDA- MB-231 cancer cells with down-regulation of PI3K. In this present investigation, we have identified the neoandrographolide of A. paniculata that had strong interaction with the PI3K which may be necessary as potential anti-cancer activities in the TNBC.