Dietary flavonoids inhibit the anti-cancer effects of the proteasome inhibitor Bortezomib


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Feng-Ting Liu1, Samir G Agrawal1, Zanyar Movasaghi2, Peter B Wyatt3, Ihtesham U Rehman2, John G Gribben4, Adrian C Newland1, Li Jia1

1Institute of Cell and Molecular Science, Queen Mary University of London, London, UK, 2Department of Materials /IRC in Biomedical Materials, Queen Mary University of London, London, UK, 3School of Biological and Chemical Sciences, Queen Mary University of London, London, UK, 4Centre for Experimental Cancer Medicine, Institute of Cancer, Queen Mary University of London, London, UK

Abstract

Dietary flavonoids have many health-promoting actions, including anti-cancer activity via proteasome inhibition. Bortezomib 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% 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 pre-incubated with quercetin, indicating a direct effect of quercetin on myeloma cells. At high doses, quercetin itself induced tumor cell death.

This data indicates that dietary flavonoids limit the efficacy of Bortezomib, while 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.

Dietary flavonoids have many health-promoting actions, including anti-cancer activity via proteasome inhibition. Bortezomib 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% 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 pre-incubated with quercetin, indicating a direct effect of quercetin on myeloma cells. At high doses, quercetin itself induced tumor cell death.

This data indicates that dietary flavonoids limit the efficacy of Bortezomib, while 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.

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