Highly Potent Antiausterity Agents from Callistemoncitrinus and Their Mechanism of Action against the PANC‑1Human Pancreatic Cancer Cell Line
2020
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.
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