Modulation of P-glycoprotein-mediated multidrug resistance by flavonoid derivatives and analogues.
Flavonoid derivatives were synthesized and tested for their ability to modulate P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) in vitro. These compounds belong to various flavonoid subclasses, namely: chromones, azaisoflavones, and aurones. Among the investigated compounds, three showed potent reversing activity. 2-(4-methylpiperazin-1-ylcarbonyl)-5-hydroxychromone (4a), 5,7-dimethoxy-3-phenyl-4-quinolone (5), and 4,6-dimethoxyaurone (6) potentiated daunorubicin cytotoxicity on resistant K562 cells. They were also able to increase the intracellular accumulation of rhodamine-123, a fluorescent molecule which acts as a probe of P-glycoprotein-mediated MDR. This suggests that these compounds act, at least in part, by inhibiting P-glycoprotein activity. The most active compound, 5-hydroxy-2-(4-methylpiperazin-1-ylcarbonyl)chromone (4a) was found to be a powerful reversal agent, more potent than cyclosporin A, used as the reference molecule. No effect was observed on MRP transport nor on cell proliferation. Little apoptosis was induced on K562S cells with 4a compared to K562R, probably due to the extrusion of the compound by Pgp.
Département de Pharmacochimie Moléculaire, UMR CNRS 5063, Faculté de Pharmacie de Grenoble, 38706 La Tronche, France.
Mohamed
M
Hadjeri
Magali
M
Barbier
Xavier
X
Ronot
Anne-Marie
AM
Mariotte
Ahcène
A
Boumendjel
Jean
J
Boutonnat
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D005419:Flavonoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005456:Fluorescent Dyes; D006801:Humans; D009336:Necrosis; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011806:Quinolinium Compounds; D020112:Rhodamine 123; D013844:Thiazoles; D014407:Tumor Cells, Cultured
C474822:5-hydroxy-2-(4-methylpiperazin-1-ylcarbonyl)chromone; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002867:Chromones; D005419:Flavonoids; D005456:Fluorescent Dyes; D010879:Piperazines; D011806:Quinolinium Compounds; D013844:Thiazoles; C075295:1,1'-(4,4,7,7-tetramethyl-4,7-diazaundecamethylene)bis-4-(3-methyl-2,3-dihydro(benzo-1,3-thiazole)-2-methylidene)quinolinium; D020112:Rhodamine 123; D003630:Daunorubicin