title: Natural polyphenols antagonize the antimyeloma activity of proteasome inhibitor bortezomib by direct chemical interaction.
abstract: Bortezomib is a therapeutic proteasome inhibitor with antimyeloma activity and polyphenols are well known compounds that exert antiproliferative effects against tumuors. We attempted to co-treat myeloma cells with bortezomib and polyphenols, anticipating a synergistic effect. However, the anticancer activity of bortezomib was blocked by the polyphenols. The structural features of the polyphenols correlated strikingly with their antagonistic effect; in particular, the presence or absence of a vicinal diol moiety was the key element for effective blockage of the anticancer function of bortezomib. We speculated that the vicinal diols in the polyphenols interact with the boronic acid of bortezomib and convert the active triangular boronic acid of bortezomib to an inactive tetrahedral boronate, thus abolishing the antimyeloma activity of bortezomib. We confirmed this hypothesis by (11)B nuclear magnetic resonance spectroscopy and an in vitro assay on multiple myeloma (MM) cell lines and primary myeloma cells from patients. Based on these findings, restriction of the intake of natural polyphenols in foods or vitamin supplements during bortezomib treatment in MM patients should be considered.
authors.affiliation: Department of Molecular and Clinical Oncology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Tae Young
authors.initials: TY
authors.lastname: Kim
authors.forename: Jongmin
authors.initials: J
authors.lastname: Park
authors.forename: Bora
authors.initials: B
authors.lastname: Oh
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Min
authors.forename: Tae-Sook
authors.initials: TS
authors.lastname: Jeong
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Lee
authors.forename: Cheolwon
authors.initials: C
authors.lastname: Suh
authors.forename: June-Won
authors.initials: JW
authors.lastname: Cheong
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Yoon
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Park
authors.forename: Dong Soon
authors.initials: DS
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000037:antagonists & inhibitors*; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects; D004347:Drug Interactions; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D009101:Multiple Myeloma / Q000178:diet therapy*; D010636:Phenols / Q000494:pharmacology*; D059808:Polyphenols; D011719:Pyrazines / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D011719:Pyrazines; D000069286:Bortezomib