Development of a Novel Quinoline Derivative as a P-Glycoprotein Inhibitor to Reverse Multidrug Resistance in Cancer Cells
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...
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MDPI AG
2019-10-01
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| Online Access: | https://www.mdpi.com/2079-7737/8/4/75 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yuanyuan Zhou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T06:02:53Z |
| format | Article |
| id | doaj.art-80855663c84e4553b34ddc49428f9c9d |
| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-12T06:02:53Z |
| publishDate | 2019-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology |
| spelling | doaj.art-80855663c84e4553b34ddc49428f9c9d2023-09-03T03:59:26ZengMDPI AGBiology2079-77372019-10-01847510.3390/biology8040075biology8040075Development of a Novel Quinoline Derivative as a P-Glycoprotein Inhibitor to Reverse Multidrug Resistance in Cancer CellsYuanyuan Zhou0Po-yee Chung1Jessica Yuen-wuen Ma2Alfred King-yin Lam3Simon Law4Kwok-wah Chan5Albert Sun-chi Chan6Xingshu Li7Kim-hung Lam8Chung-hin Chui9Johnny Cheuk-on Tang10State 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, ChinaState 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, ChinaSchool of Optometry, The Hong Kong Polytechnic University, Hong Kong 999077, ChinaGriffith Medical School, Griffith University, Gold Coast, QLD 4222, AustraliaDepartment of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, ChinaDepartment of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, ChinaState 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, ChinaState 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, ChinaState 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, ChinaMultidrug 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.https://www.mdpi.com/2079-7737/8/4/75anticancermultidrug resistancep-glycoproteinquinoline compounds |
| spellingShingle | 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 Development of a Novel Quinoline Derivative as a P-Glycoprotein Inhibitor to Reverse Multidrug Resistance in Cancer Cells Biology anticancer multidrug resistance p-glycoprotein quinoline compounds |
| title | Development of a Novel Quinoline Derivative as a P-Glycoprotein Inhibitor to Reverse Multidrug Resistance in Cancer Cells |
| title_full | Development of a Novel Quinoline Derivative as a P-Glycoprotein Inhibitor to Reverse Multidrug Resistance in Cancer Cells |
| title_fullStr | Development of a Novel Quinoline Derivative as a P-Glycoprotein Inhibitor to Reverse Multidrug Resistance in Cancer Cells |
| title_full_unstemmed | Development of a Novel Quinoline Derivative as a P-Glycoprotein Inhibitor to Reverse Multidrug Resistance in Cancer Cells |
| title_short | Development of a Novel Quinoline Derivative as a P-Glycoprotein Inhibitor to Reverse Multidrug Resistance in Cancer Cells |
| title_sort | development of a novel quinoline derivative as a p glycoprotein inhibitor to reverse multidrug resistance in cancer cells |
| topic | anticancer multidrug resistance p-glycoprotein quinoline compounds |
| url | https://www.mdpi.com/2079-7737/8/4/75 |
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