title: Flavonoid dimers as bivalent modulators for P-glycoprotein-based multidrug resistance: synthetic apigenin homodimers linked with defined-length poly(ethylene glycol) spacers increase drug retention and enhance chemosensitivity in resistant cancer cells.
abstract: Much effort has been spent on searching for better P-glycoprotein- (P-gp-) based multidrug resistance (MDR) modulators. Our approach was to target the binding sites of P-gp using dimers of dietary flavonoids. A series of apigenin-based flavonoid dimers, linked by poly(ethylene glycol) chains of various lengths, have been synthesized. These flavonoid dimers modulate drug chemosensitivity and retention in breast and leukemic MDR cells with the optimal number of ethylene glycol units equal to 2-4. Compound 9d bearing four ethylene glycol units increased drug accumulation in drug-resistant cells and enhanced cytotoxicity of paclitaxel, doxorubicin, daunomycin, vincristine, and vinblastine in drug-resistant breast cancer and leukemia cells in vitro, resulting in reduction of IC50 by 5-50 times. This compound also stimulated P-gp's ATPase activity by 3.3-fold. Its modulating activity was presumably by binding to the substrate binding sites of P-gp and disrupting drug efflux.
authors.affiliation: Department of Applied Biology and Chemical Technology and the Institute of Molecular Technology for Drug Discovery and Synthesis, The Hong Kong Polytechnic University, Hong Kong SAR.
authors.forename: Kin-Fai
authors.initials: KF
authors.lastname: Chan
authors.forename: Yunzhe
authors.initials: Y
authors.lastname: Zhao
authors.forename: Brendan A
authors.initials: BA
authors.lastname: Burkett
authors.forename: Iris L K
authors.initials: IL
authors.lastname: Wong
authors.forename: Larry M C
authors.initials: LM
authors.lastname: Chow
authors.forename: Tak Hang
authors.initials: TH
authors.lastname: Chan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D047310:Apigenin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D019281:Dimerization; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; D014747:Vinblastine; D047310:Apigenin; D004317:Doxorubicin; D000251:Adenosine Triphosphatases; D017239:Paclitaxel