title: Dietary flavonoids inhibit the anticancer effects of the proteasome inhibitor bortezomib.
abstract: Dietary flavonoids have many health-promoting actions, including anticancer activity via proteasome inhibition. Bor-tezomib is a dipeptide boronate proteasome inhibitor that has activity in the treatment of multiple myeloma but is not effective in chronic lymphocytic leukemia (CLL). Although CLL cells are sensitive in vitro to bortezomib-induced apoptosis when cultured in medium, the killing activity was blocked when cultured in 50% fresh autologous plasma. Dietary flavonoids, quercetin and myricetin, which are abundant in plasma, inhibited bortezomib-induced apoptosis of primary CLL and malignant B-cell lines in a dose-dependent manner. This inhibitory effect was associated with chemical reactions between quercetin and the boronic acid group, -RB(OH)2, in bortezomib. The addition of boric acid diminished the inhibitory effect of both quercetin and plasma on bortezomib-induced apoptosis. The protective effect was also reduced when myeloma cell lines, but not B-cell lines, were preincubated with quercetin, indicating a direct effect of quercetin on myeloma cells. At high doses, quercetin itself induced tumor cell death. These data indicate that dietary flavonoids limit the efficacy of bortezomib, whereas supplemental inorganic boric acid is able to reverse this. The complex interactions between quercetin, tumor cells, and bortezomib mean caution is required when giving dietary advice to patients.
authors.affiliation: Centre for Haematology, Institute of Cell and Molecular Science, Queen Mary University of London, London, United Kingdom.
authors.forename: Feng-Ting
authors.initials: FT
authors.lastname: Liu
authors.forename: Samir G
authors.initials: SG
authors.lastname: Agrawal
authors.forename: Zanyar
authors.initials: Z
authors.lastname: Movasaghi
authors.forename: Peter B
authors.initials: PB
authors.lastname: Wyatt
authors.forename: Ihtesham U
authors.initials: IU
authors.lastname: Rehman
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Newland
authors.forename: Li
authors.initials: L
authors.lastname: Jia
mesh_terms: D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects; D001888:Boric Acids / Q000494:pharmacology; D001897:Boronic Acids / Q000037:antagonists & inhibitors*; D000069286:Bortezomib; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D005419:Flavonoids / Q000009:adverse effects*; D016166:Free Radical Scavengers / Q000009:adverse effects; D006801:Humans; D066298:In Vitro Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000178:diet therapy / Q000188:drug therapy / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000178:diet therapy / Q000188:drug therapy / Q000473:pathology; D009101:Multiple Myeloma / Q000178:diet therapy / Q000188:drug therapy / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000037:antagonists & inhibitors*; D011794:Quercetin / Q000009:adverse effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; D001888:Boric Acids; D001897:Boronic Acids; D005419:Flavonoids; D016166:Free Radical Scavengers; D011480:Protease Inhibitors; D011719:Pyrazines; D051028:bcl-2-Associated X Protein; D000069286:Bortezomib; D045304:Cytochromes c; D011794:Quercetin; C032688:boric acid