{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:35:53Z","timestamp":1787027753455,"version":"build-2736575974"},"reference-count":39,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T00:00:00Z","timestamp":1569888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Lo Ka Chung Foundation Fund","award":["ZE20"],"award-info":[{"award-number":["ZE20"]}]},{"name":"the Lo Ka Chung Foundation Fund","award":["954P"],"award-info":[{"award-number":["954P"]}]},{"name":"the Research in Chirosciences and Chemical Biology offered by the Hong Kong Polytechnic University","award":["1-BBX8"],"award-info":[{"award-number":["1-BBX8"]}]},{"name":"Central Research Grants offered by the Hong Kong Polytechnic University","award":["G-UC11"],"award-info":[{"award-number":["G-UC11"]}]},{"name":"Central Research Grants offered by the Hong Kong Polytechnic University","award":["G-YM35"],"award-info":[{"award-number":["G-YM35"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Multidrug resistance (MDR) is one of conventional cancer chemotherapy\u2019s 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\u2019s MDR reversal effect and investigate the underlying mechanism at the molecular level. To investigate 160a\u2019s 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\u2019s 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.<\/jats:p>","DOI":"10.3390\/biology8040075","type":"journal-article","created":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T11:11:16Z","timestamp":1569928276000},"page":"75","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Development of a Novel Quinoline Derivative as a P-Glycoprotein Inhibitor to Reverse Multidrug Resistance in Cancer Cells"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3684-6126","authenticated-orcid":false,"given":"Yuanyuan","family":"Zhou","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4461-1343","authenticated-orcid":false,"given":"Po-yee","family":"Chung","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica Yuen-wuen","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Optometry, The Hong Kong Polytechnic University, Hong Kong 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2771-564X","authenticated-orcid":false,"given":"Alfred King-yin","family":"Lam","sequence":"additional","affiliation":[{"name":"Griffith Medical School, Griffith University, Gold Coast, QLD 4222, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Law","sequence":"additional","affiliation":[{"name":"Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwok-wah","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert Sun-chi","family":"Chan","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingshu","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim-hung","family":"Lam","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-hin","family":"Chui","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnny Cheuk-on","family":"Tang","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"E359","DOI":"10.1002\/ijc.29210","article-title":"Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012","volume":"136","author":"Ferlay","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1517\/13543776.17.5.511","article-title":"Multi-drug resistance and cancer","volume":"17","author":"Atalay","year":"2007","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1517\/13543776.8.12.1587","article-title":"Recent strategies for the treatment of multi-drug resistance in cancer cells","volume":"8","author":"Ojima","year":"1998","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.canlet.2014.03.013","article-title":"Multi-drug resistance in cancer chemotherapeutics: Mechanisms and lab approaches","volume":"347","author":"Wu","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"105","DOI":"10.2217\/14622416.9.1.105","article-title":"ABC multidrug transporters: Structure, function and role in chemoresistance","volume":"9","author":"Sharom","year":"2008","journal-title":"Pharmacogenomics"},{"key":"ref_6","first-page":"4186","article-title":"Phase I trial of XR9576 in healthy volunteers demonstrates modulation of P-glycoprotein in CD56(+) lymphocytes after oral and intravenous administration","volume":"6","author":"Stewart","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.biomaterials.2009.09.048","article-title":"The use of nanoparticle-mediated targeted gene silencing and drug delivery to overcome tumor drug resistance","volume":"31","author":"Patil","year":"2010","journal-title":"Biomaterials"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1016\/S0306-3623(96)00081-X","article-title":"The P-glycoprotein multidrug transporter","volume":"27","author":"Fardel","year":"1996","journal-title":"Gen. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1016\/j.phymed.2013.04.005","article-title":"In vitro to in vivo evidence of the inhibitor characteristics of Schisandra lignans toward P-glycoprotein","volume":"20","author":"Liang","year":"2013","journal-title":"Phytomedicine"},{"key":"ref_10","first-page":"159","article-title":"Nanodrug delivery in reversing multidrug resistance in cancer cells","volume":"5","author":"Govender","year":"2014","journal-title":"Front. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S0169-409X(02)00175-8","article-title":"Considerations in the design and development of transport inhibitors as adjuncts to drug therapy","volume":"55","author":"Dantzig","year":"2003","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1177\/107327480301000207","article-title":"Overcoming Multidrug Resistance in Cancer: An Update on the Clinical Strategy of Inhibiting P-Glycoprotein","volume":"10","author":"Thomas","year":"2003","journal-title":"Cancer Control"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2903","DOI":"10.1016\/j.febslet.2006.02.020","article-title":"Mechanisms and strategies to overcome multiple drug resistance in cancer","volume":"580","author":"Ozben","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/345255a0","article-title":"Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in plasmodium-falciparum","volume":"345","author":"Foote","year":"1990","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/bjc.1996.29","article-title":"MDA435\/LCC6 and MDA435\/LCC6(MDR1): Ascites models of human breast cancer","volume":"73","author":"Leonessa","year":"1996","journal-title":"Br. J. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/S0165-4608(00)00317-4","article-title":"Establishment and characterization of a new xenograft-derived human esophageal squamous cell carcinoma cell line SLMT-1 of Chinese origin","volume":"124","author":"Tang","year":"2001","journal-title":"Cancer Genet. Cytogenet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.cancergencyto.2005.07.016","article-title":"Cytogenetic aberrations in immortalization of esophageal epithelial cells","volume":"165","author":"Zhang","year":"2006","journal-title":"Cancer Genet. Cytogenet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.canlet.2019.03.011","article-title":"ABCG1 and Pgp identify drug resistant, self-renewing osteosarcoma cells","volume":"453","author":"Roundhill","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_19","unstructured":"Resh, V.H., and Card\u00e9, R.T. (2009). Chapter 39\u2014Cell Culture. Encyclopedia of Insects, Academic Press. [2nd ed.]."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nbt1284","article-title":"Relating protein pharmacology by ligand chemistry","volume":"25","author":"Keiser","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/S0960-894X(01)81162-8","article-title":"5-(3-carboxymethoxyphenyl)-2-(4,5-dimethylthiazolyl)-3-(4-sulfophenyl)tetrazolium, inner salt (MTS) and related analogs of 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) reducing to purple water-soluble formazans As cell-viability indicators","volume":"1","author":"Barltrop","year":"1991","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_22","first-page":"184","article-title":"Comparison of MTT, XTT, and a novel tetrazolium compound MTS for in vitro proliferation and chemosensitivity assays","volume":"3","author":"Riss","year":"1992","journal-title":"Mol. Biol. Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3289","DOI":"10.1021\/acs.jmedchem.6b01787","article-title":"Design, Synthesis, and Pharmacological Characterization of N-(4-(2 (6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)yl)ethyl)phenyl)quinazolin-4- amine Derivatives: Novel Inhibitors Reversing P-Glycoprotein-Mediated Multidrug Resistance","volume":"60","author":"Qiu","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_24","first-page":"97","article-title":"Synergistic combination of microtubule targeting anticancer fludelone with cytoprotective panaxytriol derived from panax ginseng against MX-1 cells in vitro: Experimental design and data analysis using the combination index method","volume":"6","author":"Zhang","year":"2016","journal-title":"Am. J. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1124\/pr.58.3.10","article-title":"Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies","volume":"58","author":"Chou","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1097\/BRS.0b013e31817e0424","article-title":"Lack of association between the promoter polymorphism of the MTNR1A gene and adolescent idiopathic scoliosis","volume":"33","author":"Qiu","year":"2008","journal-title":"Spine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1111\/j.1442-2050.2010.01070.x","article-title":"Doxorubicin, cisplatin, and fluorouracil combination therapy for metastatic esophageal squamous cell carcinoma","volume":"23","author":"Honda","year":"2010","journal-title":"Dis. Esophagus"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1124\/mol.108.053546","article-title":"Enhancement of doxorubicin cytotoxicity on human esophageal squamous cell carcinoma cells by indomethacin and 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC236) via inhibiting P-glycoprotein activity","volume":"75","author":"Yu","year":"2009","journal-title":"Mol. Pharmacol."},{"key":"ref_29","first-page":"389","article-title":"Levels of multidrug resistance (MDR1) P-glycoprotein expression by human breast cancer correlate with in vitro resistance to taxol and doxorubicin","volume":"4","author":"Mechetner","year":"1998","journal-title":"Clin. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1006\/abbi.1993.1311","article-title":"Characterization of the Cellular Reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT): Subcellular Localization, Substrate Dependence, and Involvement of Mitochondrial Electron Transport in MTT Reduction","volume":"303","author":"Berridge","year":"1993","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Tayebi, L., and Moharamzadeh, K. (2017). 7\u2014Characterization of biomaterials. Biomaterials for Oral and Dental Tissue Engineering, Woodhead Publishing.","DOI":"10.1016\/B978-0-08-100961-1.00001-3"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Meng, J.R., Dai, B.B., Fang, B.L., Bekele, B.N., Bornmann, W.G., Sun, D.L., Peng, Z.H., Herbst, R.S., Papadimitrakopoulou, V., and Minna, J.D. (2010). Combination Treatment with MEK and AKT Inhibitors Is More Effective than Each Drug Alone in Human Non-Small Cell Lung Cancer In Vitro and In Vivo. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0014124"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"797","DOI":"10.18632\/oncotarget.343","article-title":"Propranolol potentiates the anti-angiogenic effects and antitumor efficacy of chemotherapy agents: Implication in breast cancer treatment","volume":"2","author":"Pasquier","year":"2011","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1097\/00001813-199607000-00012","article-title":"Ranking of P-glycoprotein substrates and inhibitors by a calcein-AM fluorometry screening assay","volume":"7","author":"Tiberghien","year":"1996","journal-title":"Anti-Cancer Drugs"},{"key":"ref_35","first-page":"1053","article-title":"Combinations of P-glycoprotein blockers, verapamil, PSC833, and cremophor act differently on the multidrug resistance associated protein (MRP) and on P-glycoprotein (Pgp)","volume":"19","author":"Aszalos","year":"1999","journal-title":"Anticancer Res."},{"key":"ref_36","first-page":"749","article-title":"In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576","volume":"61","author":"Mistry","year":"2001","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"12716","DOI":"10.1038\/s41598-018-30984-8","article-title":"Mapping discontinuous epitopes for MRK-16, UIC2 and 4E3 antibodies to extracellular loops 1 and 4 of human P-glycoprotein","volume":"8","author":"Vahedi","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/cddis.2016.381","article-title":"A mechanism for overcoming P-glycoprotein-mediated drug resistance: Novel combination therapy that releases stored doxorubicin from lysosomes via lysosomal permeabilization using Dp44mT or DpC","volume":"7","author":"Seebacher","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1146\/annurev.pharmtox.38.1.389","article-title":"In vitro and in vivo drug interactions involving human CYP3A","volume":"38","author":"Thummel","year":"1998","journal-title":"Annu. Rev. Pharmacol. Toxicol."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/8\/4\/75\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:26:48Z","timestamp":1760189208000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/8\/4\/75"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,1]]},"references-count":39,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["biology8040075"],"URL":"https:\/\/doi.org\/10.3390\/biology8040075","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,1]]}}}