ent-8(14),15-Pimaradiene-2β,19-diol, a diterpene from Aleuritopteris albofusca, inhibits growth and induces protective autophagy in hepatocellular carcinoma cells

A new pimarane-type diterpene, ent-8(14),15-pimaradiene-2β,19-diol (JXE-23), was isolated from the fern plant Aleuritopteris albofusca by our previous work; however, the biological activity of this diterpene remains unclear. In the present study, the anti-cancer potential of JXE-23 in various Cancer cells was investigated. Among MCF-7 breast Cancer cells, A549 lung Cancer cells, and HepG2 liver Cancer cells, JXE-23 displayed significant cytotoxicity to HepG2 cells with an IC₅₀ value of 17.20 ± 1.73 µM, while showing no obvious toxicity in normal hepatocytes HL7702. JXE-23 inhibited cell growth and colony formation in HepG2 cells. A cell cycle distribution analysis showed that JXE-23 caused G2/M cell cycle arrest. Besides, JXE-23 also suppressed the migration of HepG2 cells. Interestingly, an increase of LIGHT chain 3 II (LC3II) and Beclin 1 and a decrease of P62 have occurred in JXE-23-treated cells, as well as the formation of GFP-LC3 dots, indicative of Autophagy induction by JXE-23. When combined with Autophagy Inhibitor 3-methyladenine and chloroquine, the cell viability was significantly reduced, suggesting that JXE-23 triggered protective Autophagy in hepatoma cells. Further study showed that JXE-23 inactivated the CIP2A/p-AKT/c-Myc signaling axis in HepG2 cells. Our data provided evidence that JXE-23 inhibited cell growth, arrested cells at the G2/M phase, and induced protective Autophagy in HepG2 hepatocellular carcinoma cells. JXE-23 may be a potential lead compound for anti-cancer drug development, and Autophagy Inhibitor treatment may provide an effective strategy for improving its anti-cancer effect.

ent-8(14),15-Pimaradiene-2β,19-diol (JXE-23); Autophagy; CIP2A; Cell cycle; Hepatocellular carcinoma.