Title: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
Volume: 17
Issue: 5
Author(s): Wen-Tsan Chang, Yao Fong, Shih-Chang Chuang, Chon-Kit Chou, Han-Lin Chou, Chun-Feng Yang, Chih-Hua Tseng, Yeh-Long Chen*Chien-Chih Chiu*
Affiliation:
- Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807,Taiwan
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan, 100, Shih-Chuan 1st Road, Kaohsiung, 80708,Taiwan
Keywords:
BPIQ, quinoline, HCC, DNA damage, apoptosis, ER stress, survivin, XIAP, γH2AX.
Abstract: 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 the quinoline derivative, 9-bis[2-(pyrrolidin-1-yl)ethoxy]-6-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-11Hindeno[
1,2-c]quinolin-11-one (BPIQ) exerts the inhibitory potential against several cancer cells, including liver cancer
cells.
Objective: We further investigated the anti-HCC effects of BPIQ, including apoptosis and the modulation of ER stress.
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 apoptosis. Western blot assay was conducted for detecting the changes in apoptosis- and
endoplasmic reticulum (ER) stress-associated proteins.
Results: BPIQ inhibits cell growth and induces the apoptosis of both Ha22T and Huh7 cell lines significantly. The
level of γH2AX, an endogenous DNA damage biomarker was dramatically increased suggesting the involvement of
DNA damage pathway in BPIQ-induced apoptosis. Further, BPIQ down-regulates the pro-survival proteins, survivin,
XIAP and cyclin D1. BPIQ also may regulate ER stress response through modulating the 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 occur 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.
