Polyditerpene acid from Pinus koraiensis pinecones inhibits the progression of hepatocarcinoma

The extracts of Pinus koraiensis pinecones have been proved to be highly cytotoxic to tumor cells, with ambiguous material basis of antitumor efficacy. In the present study, screening of compounds with antitumor activity was performed through successive applications of various purification technologies, accompanied with anticancer activity tracking. Futhermore, structures of target molecules were confirmed. In order to obtain highly active compounds, the lead compound dehydroabietic acid was chemically modified into its hexamer (DD2) by a simple method and its mechanisms for antitumor were explored in vivo and in vitro by some cell phenotype experiments, western blot, immunohistochemistry, TUNEL assay. Results showed that cytotoxins composed of 5-hydroxydehydroabietic acid, dehydroabietic acid, 15-hydroxy-7-oxodehydroabietic acid, 7α-hydroxydehydroabietic acid and inonotusic acid, exerted the synergistic antitumor effects against HepG2 cells. Especially, polymerization of multiple tricyclic skeletons effectively increased the cytotoxicity of dehydroabietic acid to tumor cells. Notably, DD2 exhibited stronger antitumor efficacy in vitro and in vivo mainly through the induction of G2/M cell cycle arrest and mitochondria apoptosis involving p53-Puma-Bcl-2/Bax axis. The analysis of liver / kidney function and HE staining demonstrated the no/low in vivo toxicity of DD2 to BALB/c nude mice. The findings will provide the theoretical reference to the discovery of new antitumor drugs and chemical modification of abietane diterpenoids.