Anticancer Potential of Eudesmanolides Derived from Sphagneticola trilobata against Colorectal Cancer, by Targeting β-catenin Signalling

INTRODUCTION: The role of β-catenin signalling in the pathogenesis of Colorectal Cancer (CRC) is indisputable. In this study, we report the identification of a cytotoxic fraction that targets the β-catenin signalling axis in colorectal cancer cells. METHODS: Chromatographic and spectrometric techniques were used for the isolation and phytochemical characterization of Eudesmanolides (EDS). Cell-viability assays, flow cytometry, fluorescent microscopy, immunoblot analysis, qRT-PCR, and in silico molecular docking studies were used to analyse the antitumor potential of EDS against CRC cells. Toxicological evaluation of EDS was conducted in Swiss albino mice. RESULTS: We have isolated and characterized the bioactive fraction designated EDS, consisting of the eudesmanolides, namely wedelolide D and prostrolide A, from the Ethyl Acetate (EA) leaf extract of the plant Sphagneticola trilobata (S. trilobata). EDS was found to be highly efficacious against CRC cells and induced an apoptotic mode of cell death in different CRC cell lines. Delineation of the apoptotic pathway induced by EDS revealed extrinsic pathway activation and amplification of the apoptotic signals via the intrinsic pathway through truncated-BID. Molecular investigations revealed EDS-mediated inhibition of β-catenin signalling and PPAR-γ (peroxisome proliferator-activated receptor gamma) activation in HCT116 CRC cells. DISCUSSION: Our study revealed that EDS induced strong apoptotic signals in CRC cells, initiated at the cell surface, resulting in apoptosis involving extrinsic and intrinsic mechanisms irrespective of the p53 status or molecular phenotype of CRC cells. In addition, PPAR-γ activation by EDS resulted in the suppression of β- catenin nuclear accumulation and the subsequent inhibition of proliferative and survival signalling. Moreover, EDS was found to be pharmacologically safe. CONCLUSION: To summarize, we demonstrate, with mechanism-based evidence, the chemotherapeutic efficacy of EDS, comprising the eudesmanolides, wedelolide D, and prostrolide A, derived from S. trilobata, against CRC. The potential of these lead-structures are worth exploring for their beneficial effects in combination with other therapeutic interventions.