Development of a Novel Quinoline Derivative as a P-Glycoprotein Inhibitor to Reverse Multidrug Resistance in Cancer Cells
Yuanyuan Zhou,
Po-yee Chung,
Jessica Yuen-wuen Ma,
Alfred King-yin Lam,
Simon Law,
Kwok-wah Chan,
Albert Sun-chi Chan,
Xingshu Li,
Kim-hung Lam,
Chung-hin Chui,
Johnny Cheuk-on Tang
Affiliations
Yuanyuan Zhou
State Key Laboratory of Chemical Biology and Drug Discovery, Lo Ka Chung Centre for Natural Anticancer Drug Development, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong 999077, China
Po-yee Chung
State Key Laboratory of Chemical Biology and Drug Discovery, Lo Ka Chung Centre for Natural Anticancer Drug Development, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong 999077, China
Jessica Yuen-wuen Ma
School of Optometry, The Hong Kong Polytechnic University, Hong Kong 999077, China
Alfred King-yin Lam
Griffith Medical School, Griffith University, Gold Coast, QLD 4222, Australia
Simon Law
Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
Kwok-wah Chan
Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China
Albert Sun-chi Chan
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
Xingshu Li
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
Kim-hung Lam
State Key Laboratory of Chemical Biology and Drug Discovery, Lo Ka Chung Centre for Natural Anticancer Drug Development, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong 999077, China
Chung-hin Chui
State Key Laboratory of Chemical Biology and Drug Discovery, Lo Ka Chung Centre for Natural Anticancer Drug Development, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong 999077, China
Johnny Cheuk-on Tang
State Key Laboratory of Chemical Biology and Drug Discovery, Lo Ka Chung Centre for Natural Anticancer Drug Development, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong 999077, China
Multidrug resistance (MDR) is one of conventional cancer chemotherapy’s limitations. Our group previously synthesized a series of quinoline-based compounds in an attempt to identify novel anticancer agents. With a molecular docking analysis, the novel compound 160a was predicted to target p-glycoprotein, an MDR candidate. The purpose of this study is to evaluate 160a’s MDR reversal effect and investigate the underlying mechanism at the molecular level. To investigate 160a’s inhibitory effect, we used a series of parental cancer cell lines (A549, LCC6, KYSE150, and MCF-7), the corresponding doxorubicin-resistant cell lines, an MTS cytotoxicity assay, an intracellular doxorubicin accumulation test, and multidrug resistance assays. The Compusyn program confirmed, with a combination index (CI) value greater than 1, that 160a combined with doxorubicin exerts a synergistic effect. Intracellular doxorubicin accumulation and transported calcein acetoxymethyl (AM) (a substrate for p-glycoprotein) were both increased when cancer cells with MDR were treated with compound 160a. We also showed that compound 160a’s MDR reversal effect can persist for at least 1 h. Taken together, these results suggest that the quinoline compound 160a possesses high potential to reverse MDR by inhibiting p-glycoprotein-mediated drug efflux in cancer cells with MDR.
