Exploring the apoptosis-inducing potential of Syzygium cimini leaves in cancer treatment; LC-ESI-MS/MS analysis, biological assessments, and computational studies

This study provides a novel, integrated phytochemical and biological profiling of S. cumini leaves, differentiating it through its computational and experimental focus on the caspase-mediated apoptotic pathway. Herein, sixty-nine (69) compounds were tentatively identified in the methanol extract of Syzygium cumini leaves, with 45 of these compounds found only in the hexane extract. The IC 50s of the methanol extract of Syzygium cumini leaves were recorded towards eight diverse cancer cell lines. The methanol extract showed very strong anticancer activities against MDA-MB-468, HEPG2, and H1299 cancer cells with IC 50 values of 13.16, 10.60, and 20.55 µg/mL, respectively. Furthermore, the methanol extract of Syzygium cumini leaves was further examined for its apoptotic potential as a proposed mechanism for its anticancer activity. Interestingly, the expression of the proapoptotic markers (Caspases 3, 6, and 7, and BAX) was upregulated with a fold change of 1.29, 2.02, 1.95, and 3.52, respectively. On the other hand, the expression of anti-apoptotic proteins (MMP2, MMP9, and Bcl-2) was dramatically decreased by 1.78, 1.84, and 2.07-fold change, respectively. Additionally, a molecular docking study against Caspase 6 clarified that kaempferol malonyl-hexoside, kaempferol- O -( p -coumaroyl)-hexoside, and quercetin- O -hexoside-pentoside showed superior docking scores compared to the Co-crystal inhibitor. Moreover, a molecular dynamics simulation for 500 ns was implemented to validate the docking results and confirm the stability of these compounds within the active site of the Caspase 6 enzyme. Additionally, the MM-GBSA calculations and ADME pharmacokinetic properties were evaluated.