Bortezomib and EGCG: no green tea for you?

S ince the first description of its clinical activity against multiple myeloma and mantle cell lymphoma, the proteasome inhibitor bortezomib has become a standard of care for patients with these diseases in the relapsed/refractory setting. Modulation of proteasome function has also become an established approach to overcome chemoresistance and achieve chemosensitization in patients with relapsed/refractory and newly diagnosed myeloma, making bortezomib a crucial part of our chemotherapeutic armamentarium. Importantly, Golden et al have found that polyphenolic components of green tea, including (-)-Epigallocatechin gallate (EGCG), antagonized bortezomib in preclinical in vitro and in vivo model systems.1 EGCG inhibited the antiproliferative effects of bortezomib on myeloma cell lines; prevented bortezomib from inhibiting the proteasome, inducing caspase-7 cleavage and activating the unfolded protein response; and protected xenografts from the proapoptotic effects of this and other peptidylboronate inhibitors, but not of nonboronate proteasome inhibitors. Presumably, this occurred as a result of a direct interaction leading to formation of a covalent cyclic boronate between EGCG and bortezomib (see figure), which was then no longer able to bind to the N-terminal threonine active site of the chymotrypsin-like proteasome moiety. EGCG is only one of many polyphenols found in green tea that are classified as flavonoids, with others including epigallocatechin and epicatechin, both of which were found to inhibit bortezomib as well, although with less potency. If all compounds containing 1,2-diol groups were to have a similar activity, then black tea, which also has a number of important polyphenolic constituents including theaflavins and thearubigins, could inhibit bortezomib as well. Other compounds in this class would include myricetin and quercetin, the latter of which has already been found to bind and inhibit bortezomib.2 Quercetin is another flavonoid that can be found at appreciable concentrations in foods, such as capers, leafy green vegetables, red onions, red grapes, red apples, and a number of berries, among other sources.3 Interestingly, epinephrine, norepinephrine, and dopamine, all of which are derived from catechol, bear 1,2-diols, and boronates can also be bound by 1,3-diols based on resorcinol. This by no means exhaustive list clearly indicates that green tea may represent only the beginning of this story rather than its end. Do these findings support a recommendation to patients that they avoid the use of green and black teas and flavonoid-containing foods, such as those described above, including chocolate? At least in the case of green tea, EGCG concentrations of 2.5 M or higher were needed to see inhibition of bortezomib’s activity, which were well above the maximal concentrations detected in one phase 1 trial that studied this agent’s pharmacokinetics.4 While such levels were achieved in a follow-up trial,5 this required that patients ingest, preferably in a fasting state, large doses of Polyphenon E. This decaffeinated green tea catechin extract contained about 60% EGCG, which represents a much greater content of this polyphenol than that found in brewed green tea.6 Alsoof note, pharmacokinetic studies of bortezomib after a standard dose of 1.3 mg/ m2 have revealed plasma concentrations up to 187.03 ng/mL,7,8 or greater than 450 nM. In contrast, Golden et al show that bortezomib at