Cytotoxic 6,12-guaianolides from Himalaiella heteromalla (D.Don) Raab-Straube: mechanistic investigations in pancreatic cancer cells.

A series of five known 6,12-guaianolides (1-5) was isolated from the leaves of the Indian Himalayan herb, Himalaiella heteromalla (D.Don) Raab-Straube, and their structures were elucidated using mass spectrometry and NMR. All compounds are reported for the first time from this plant species, with compound 3 representing the first isolation within the entire Himalaiella genus. Cytotoxic evaluations revealed compound 3 as the most potent against MIA PaCa-2 pancreatic cancer cells (IC50: 2.27 ± 0.09 µM). Mechanistic studies confirmed that compound 3 induced apoptosis, mitochondrial dysfunction, and G2/M phase cell cycle arrest. Molecular docking revealed the efficient binding of compound 3 to Bcl-2 (-7.6 kcal/mol), a key anti-apoptotic protein, supported by western blot analysis showing downregulation of Bcl-2. These findings indicate that compound 3 exerts its anticancer effects by inducing apoptosis and arresting the cell cycle at the G2/M phase, thereby highlighting its potential as a therapeutic lead.