Apoptotic/cell cycle arrest potential of dusty miller methanol extract against Paca-2 pancreatic cancer cells via upregulating Bax/Bcl2: A HPLC-ESI-MS/MS, GNPS-based molecular networking and network pharmacology studies.

Cancer continues to be a major worldwide health problem, necessitating the continuous discovery of novel therapeutics. The current study investigated the anti-cancer potential of Jacobaea maritima (JM) and Tradescantia pallida (TP) extracts via MTT assay. Initial screening revealed JM's superior cytotoxicity across multiple human cancer cell lines (lung, pancreatic, colon, breast, osteosarcoma), with maintaining moderate safety on normal cells, while TP showed limited activity. Further analysis highlighted JM's potent effect on the pancreatic cells (Paca2) (IC50 = 29.1 μg/mL), where it induced apoptosis via upregulating pro-apoptotic Bax and downregulating anti-apoptotic Bcl2, and caused G₁ phase cell cycle arrest, confirmed by flow cytometry. LC-ESI-MS/MS metabolomic profiling in combination with GNPS-based molecular networking identified 74 metabolites, most of which are phenolics. Network pharmacology predicted that JM-derived phenolics target pancreatic cancer-related proteins, notably EGFR and STAT3, suggesting a multi-compound and multi-target mechanism. Molecular docking further supported the results, and highlighted rosmarinic acid which revealed a promising binding to EGFR. In conclusion, Jacobaea maritima extract exhibit a significant anti-cancer activity by inducing apoptosis and cell cycle arrest, likely through modulating key oncogenic pathways. This study sheds light on Jacobaea maritima as a promising natural source for developing novel cancer therapies.