Please use this identifier to cite or link to this item:
http://hdl.handle.net/10397/105780
DC Field | Value | Language |
---|---|---|
dc.contributor | Department of Applied Biology and Chemical Technology | - |
dc.creator | Kan, JWY | - |
dc.creator | Yan, CSW | - |
dc.creator | Wong, ILK | - |
dc.creator | Su, X | - |
dc.creator | Liu, Z | - |
dc.creator | Chan, TH | - |
dc.creator | Chow, LMC | - |
dc.date.accessioned | 2024-04-23T04:31:14Z | - |
dc.date.available | 2024-04-23T04:31:14Z | - |
dc.identifier.issn | 1661-6596 | - |
dc.identifier.uri | http://hdl.handle.net/10397/105780 | - |
dc.language.iso | en | en_US |
dc.publisher | MDPI AG | en_US |
dc.rights | Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). | en_US |
dc.rights | The following publication Kan JWY, Yan CSW, Wong ILK, Su X, Liu Z, Chan TH, Chow LMC. Discovery of a Flavonoid FM04 as a Potent Inhibitor to Reverse P-Glycoprotein-Mediated Drug Resistance in Xenografts and Improve Oral Bioavailability of Paclitaxel. International Journal of Molecular Sciences. 2022; 23(23):15299 is available at https://doi.org/10.3390/ijms232315299. | en_US |
dc.subject | Flavonoids | en_US |
dc.subject | Modulator | en_US |
dc.subject | Multidrug resistance | en_US |
dc.subject | Oral bioavailability | en_US |
dc.subject | P-glycoprotein | en_US |
dc.title | Discovery of a flavonoid FM04 as a potent inhibitor to reverse P-glycoprotein-mediated drug resistance in xenografts and improve oral bioavailability of paclitaxel | en_US |
dc.type | Journal/Magazine Article | en_US |
dc.identifier.volume | 23 | - |
dc.identifier.issue | 23 | - |
dc.identifier.doi | 10.3390/ijms232315299 | - |
dcterms.abstract | Biotransformation of flavonoid dimer FD18 resulted in an active metabolite FM04. It was more druggable because of its improved physicochemical properties. FM04 (EC50 = 83 nM) was 1.8-fold more potent than FD18 in reversing P-glycoprotein (P-gp)-mediated paclitaxel (PTX) resistance in vitro. Similar to FD18, FM04 chemosensitized LCC6MDR cells towards multiple anticancer drugs by inhibiting the transport activity of P-gp and restoring intracellular drug levels. It stimulated the P-gp ATPase by 3.3-fold at 100 μM. Different from FD18, FM04 itself was not a transport substrate of P-gp and presumably, it cannot work as a competitive inhibitor. In the human melanoma MDA435/LCC6MDR xenograft, the co-administration of FM04 (28 mg/kg, I.P.) with PTX (12 mg/kg, I.V.) directly modulated P-gp-mediated PTX resistance and caused a 56% (*, p < 0.05) reduction in tumor volume without toxicity or animal death. When FM04 was administered orally at 45 mg/kg as a dual inhibitor of P-gp/CYP2C8 or 3A4 enzymes in the intestine, it increased the intestinal absorption of PTX from 0.2% to 14% in mice and caused about 57- to 66-fold improvement of AUC as compared to a single oral dose of PTX. Oral co-administration of FM04 (45 mg/kg) with PTX (40, 60 or 70 mg/kg) suppressed the human melanoma MDA435/LCC6 tumor growth with at least a 73% (***, p < 0.001) reduction in tumor volume without serious toxicity. Therefore, FM04 can be developed into a novel combination chemotherapy to treat cancer by directly targeting the P-gp overexpressed tumors or potentiating the oral bioavailability of P-gp substrate drugs. | - |
dcterms.accessRights | open access | en_US |
dcterms.bibliographicCitation | International journal of molecular sciences, Dec. 2022, v. 23, no. 23, 15299 | - |
dcterms.isPartOf | International journal of molecular sciences | - |
dcterms.issued | 2022-12 | - |
dc.identifier.scopus | 2-s2.0-85143589271 | - |
dc.identifier.pmid | 36499627 | - |
dc.identifier.eissn | 1422-0067 | - |
dc.identifier.artn | 15299 | - |
dc.description.validate | 202404 bcch | - |
dc.description.oa | Version of Record | en_US |
dc.identifier.FolderNumber | OA_Scopus/WOS | en_US |
dc.description.fundingSource | Others | en_US |
dc.description.fundingText | Health and Medical Research Fund; Project of Strategic Importance of the Hong Kong Polytechnic University; State Key Laboratory of the Chemical Biology and Drug Discovery | en_US |
dc.description.pubStatus | Published | en_US |
dc.description.oaCategory | CC | en_US |
Appears in Collections: | Journal/Magazine Article |
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File | Description | Size | Format | |
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ijms-23-15299.pdf | 4.45 MB | Adobe PDF | View/Open |
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