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

Abstract

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 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.

Condensed tannins from Ulmus pumila L. leaves induce G2 /M phase arrest and apoptosis via caspase‐cascade activation in TFK ‐1 cholangiocarcinoma cells

“…Considering that the cell cycle plays a pivotal role in cell growth, we also evaluated the effect of UCTs on cell cycle of TFK‐1 cells. Consistent with previous studies (Jin et al, 2018; Li et al, 2018; Zhang et al, 2018), our results showed that the TFK‐1 cells treated with UCTs markedly induced cell cycle arrest at the G2/M phase (Figure 3b,c). According to the report by Pardee (1989), G2/M can arrest the termination of DNA synthesis resulting in inability of tumor cells to complete normal cell division, which ultimately leads to cell death and inhibits tumor proliferation.…”

“…Consistent with previous studies (Jin et al, 2018;Li et al, 2018;Zhang et al, 2018), our results showed that the TFK-1 cells treated with UCTs markedly induced cell cycle arrest at the G2/M phase (Figure 3b,c). According to the report by Pardee (1989) treatment is a feasible approach to prevent tumor development by eliminating those cells that have been inappropriately induced to proliferate (Singh et al, 2011).…”

Clinical significance of long non-coding RNA DUXAP8 and its protein coding genes in hepatocellular carcinoma

“…It exerts antitumor effects with high activity and low toxicity (56). Moreover, cinchonine inhibited cell proliferation and promoted apoptosis by activating caspase-3 dependence in human liver cancer cells (57). Similarly, it was reported that cinchonine induced apoptosis of Hela and A549 cells by targeting TRAF6, suggesting that cinchonine has antitumor effects (58).…”

Inhibition of Porcine Epidemic Diarrhea Virus by Cinchonine via Inducing Cellular Autophagy

“…In the studies on PEDV, it was demonstrated that 2-Deoxy-D-glucose (2-DG) can trigger UPR which in turn can lead to the suppression of PEDV infection in vitro . In addition, further studies have indicated that cinchonine could activate ER stress through promoting PERK and eIF2α phosphorylation ( Jin et al., 2018 ). This aroused our interest to explore whether cinchonine also can exhibit its anti-PEDV by activating ER stress.…”