A Shikonin Derivative Induces Excessive Autophagy in Pancreatic Cancer Cells

Innovative therapeutic strategies for pancreatic cancer have become an increasingly prominent area of biomedical research. Natural compounds, prized for their structural complexity and diverse bioactivities, remain a valuable source for drug discovery. Shikonin (SHK), a naturally occurring naphthoquinone, has demonstrated potent anti-tumor properties across various cancer types. This study synthesized a series of SHK derivatives via olefin metathesis to investigate the functional role of the isohexenyl side chain. Among the synthesized compounds, S6 bearing a fluorophenyl group showed enhanced anti-pancreatic cancer activity, achieving a 50% inhibitory concentration of 0.9 µM against AsPC-1 cells within 24 h. Mechanistic analysis showed that S6 inhibited the AKT and mTOR signaling pathways, leading to excessive autophagy and significantly reducing the proliferation and migration of pancreatic cancer cells. In vivo assessments further demonstrated a dose-dependent reduction in tumor volume following S6 treatment, highlighting its potential as a promising candidate for pancreatic cancer therapy.