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 exerting antiproliferative effects against tumors. We attempted cotreatment of 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 infer 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, which abolishes the antimyeloma activity of bortezomib. We confirmed this hypothesis by 11B NMR spectroscopy and an in vitro assay on myeloma 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 multiple myeloma patients should be considered.