9-bis[2-(pyrrolidin-1-yl)ethoxy]-6-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-11H-indeno[1, 2-c]quinolin-11-one (BPIQ), A Quinoline Derivative Inhibits Human Hepatocellular Carcinoma Cells by Inducing ER Stress and Apoptosis.

Background: Hepatocellular carcinoma (HCC) is one of the leading cancers in the world, including Taiwan. The chemoresistance of advanced HCC frequently results in the poor prognosis of patients. Previous studies demonstrated that a quinoline derivative, 9-bis[2-(pyrrolidin-1-yl)ethoxy]-6-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-11H-indeno[1,2-c]quinolin-11-one (BPIQ) exerts the inhibitory potential against several cancer cells, including liver cancer cells. In the study, we further investigated at BPIQ for its anti-HCC cancer activities. Methods: Both trypan blue exclusion assay and colony formation assay were performed to examine whether BPIQ affects the growth of HCC cell lines Ha22T and Huh7. Flow cytometry-based assay was performed for determining the cell cycle distribution and apoptotic cell death. Western blot assay was conducted for detecting the changes of apoptosis- and endoplasmic reticulum (ER) stress-associated proteins. Results: The results of cellular proliferation assay showed that BPIQ significantly inhibits the growth of two tested HCC cell lines Ha22T and Huh7. Our results showed that BPIQ inhibits cell growth and induces the apoptosis of both two cell lines significantly. Furthermore, the level of γH2AX, an endogenous DNA damage biomarker was dramatically increased, suggesting the involvement of DNA damage pathway in BPIQ-induced apoptosis. The results of Western blotting showed that BPIQ treatment down-regulates pro-survival proteins, survivin, XIAP and cyclin D1. On the contrary, BPIQ also may regulate ER stress response through modulating the expression levels of ER stress-related proteins Glucose-regulated protein of 78 kD (GRP78), Inositol-requiring kinase-1α (IREα), C/EBP homologous protein (Chop) and calnexin. Conclusions: The anti-HCC effect of BPIQ may through down-regulating pro-survival proteins, and the modulation of ER stress may contribute to the BPIQ-induced apoptosis of HCC cells. The chemotherapeutic or chemopreventive applications of BPIQ for HCC treatment will be worthy of further investigation in future.