Cinchonine activates endoplasmic reticulum stress-induced apoptosis in human liver cancer cells

Cinchonine is a natural compound present in Cinchona bark. It exerts multidrug resistance reversal activity and synergistic apoptotic effect with paclitaxel in uterine sarcoma cells. Whether cinchonine is effective against human liver cancer, however, remains elusive. A total of five liver cancer cell lines including Bel-7402, MHCC97H, HepG2, Hep3B and SMCC7721 were used. The anti-proliferative effects of cinchonine on these liver cancer cell lines were assessed by MTT assay. The apoptotic effects of cinchonine on liver cancer cell lines were assessed by flow cytometry with Annexin V/propidium iodide assay. Caspase-3 activation, poly (ADP-Ribose) polymerase (PARP) cleavage as well as the endoplasmic-reticulum (ER) stress response was detected by western blotting. Balb/c-nude mice bearing HepG2 xenograft tumors were used to evaluate the in vivo antitumor effect of cinchonine. It was demonstrated that cinchonine inhibited cell proliferation and promoteed apoptosis in liver cancer cells in a dose-dependent manner. Cinchonine promoted caspase-3 activation and PARP1 cleavage in liver cancer cells. Furthermore, cinchonine activated the ER stress response by upregulating GRP78 and promoting PERK and Eukaryotic Translation Initiation Factor 2 α phosphorylation. The Balb/c-nude mice experiment revealed that cinchonine suppressed HepG2 xenograft tumor growth in mice. The findings indicated that cinchonine promoted ER stress-induced apoptosis in liver cancer cells and suggested that cinchonine may have a potential beneficial effect for liver cancer treatment.