Highly Potent Antiausterity Agents from Callistemon citrinus and Their Mechanism of Action against the PANC-1 Human Pancreatic Cancer Cell Line

Human pancreatic cancer cells display remarkable tolerance to nutrition starvation that help them to survive in a hypovascular tumor microenvironment, a phenomenon known as "austerity". The elucidation of agents countering this tolerance is an established antiausterity strategy in anticancer drug discovery. In this study, a Callistemon citrinus leaf extract inhibited the viability of PANC-1 human pancreatic cancer cells preferentially under nutrient-deprived medium (NDM) with a PC50 value of 7.4 μg/mL. Workup of this extract resulted in the isolation of three new meroterpenoids, callistrilones L-N (1-3), together with 14 known compounds (4-17). The structure elucidation of the new compounds was achieved by HRFABMS and by NMR and ECD spectroscopic analysis. The new compounds showed highly potent preferential cytotoxicity against PANC-1 cells with PC50 values ranging from 10 to 65 nM in NDM. Of these, callistrilone L (1) inhibited PANC-1 cell migration and colony formation in a normal nutrient-rich condition. Callistrilone L (1) also strongly suppressed the migration of PANC-1 cells in real time. Mechanistically, 1 was found to inhibit the Akt/mTOR and autophagy activation pathway. Callistrilone L (1) and related meroterpenoids are promising leads for anticancer drug development based on the antiausterity strategy used in this work.