(−)-Epigallocatechin-3-Gallate (EGCG), Green Tea Component, Antagonize the Anti-Myeloma Activity of Proteasome Inhibitor PS-341 by Direct Chemical Interaction.

PS-341 (also known as bortezomib, Velcade®) has a remarkable anti-myeloma acitivity and is also potential candidate for the treatment of other tumors either alone or in combination with other chemotherapeutic agents. Investigations on the effectiveness of PS-341 in combination with other anti-neoplastic agents are currently under clinical trial. Since (−)-epigallocatechin-3-gallate (EGCG) has been reported its anti-cancer activity in various cancer types, we tried a co-treatment of PS-341 with EGCG on myeloma cells, expecting a synergistic effect. However, the anti-cancer activity of PS-341 was blocked by EGCG without any synergistic effect. At the early stage of our research, we suspected antioxidant function of EGCG is the main cause of antagonistic effect on PS-341-induced cell death. Thus we selected polyphenols showing strong antioxidant function including vitamin C. But, we did not obtain any consistant data that support the significant correlation of antioxidant function of polyphenols with antagonistic effects. Instead, the structural features of polyphenols showed striking correlations with antagonistic effect; especially the presence or absence of vicinal diol moiety on polyphenol was the key elements for the effective blocking on anti-cancer function of PS-341. We infer that vicinal diols on polyphenols interact with boronic acid of PS-341, which convert active triangular boronic acid (sp² character) of PS-341 to inactive tetrahedral boronate (sp³ character) through direct chemical interaction. The equilibrium of this conversion is controlled by structures and concentration of polyphenols, and this conversion abolished the anti-myeloma activity of PS-341. We confirmed our hypothesis on direct chemical interaction of PS-341 with EGCG through ¹¹B NMR experiment and cell viability assay data clearly support the antagonistic interaction between PS-341 and polyphenols in multiple myeloma cell lines and primary myeloma cells from patients. Based on our researches, restriction of the intake of natural polyphenols by food or vitamin supplements should be considered during the treatment with PS-341 in MM patients.

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