Since 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 peptidyl-boronate 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 μM 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 20 to 40 nM is able to largely overcome the inhibitory impact of a 2.5- to 5.0-μM concentration of EGCG. These considerations argue against the possibility that even high levels of EGCG ingestion would impact upon the clinical efficacy of bortezomib.
Nonetheless, these data serve as an always timely reminder for healthcare providers of the importance of eliciting a complete history from patients and their families, including concomitant medications and over-the-counter supplements. The risks of such drug interactions are very real, whether they involve bortezomib and EGCG, bortezomib and vitamin C,9 cyclophosphamide and curcumin,10 or any of the other myriad possibilities. Moreover, they highlight the need for additional and careful studies along the lines of Golden et al, using physiologically relevant model systems to evaluate such possible interactions. Finally, they remind us of the words “moderation in all things” attributed to the Roman playwright Publius Terentius Afer, which should especially apply to any supplements used in the setting of chemotherapy.
D.J.K. acknowledges support from the American Cancer Society (PF-07-112-01-CDD 01). R.Z.O., a Leukemia & Lymphoma Society Scholar in Clinical Research, acknowledges support from the Leukemia & Lymphoma Society (6096-07), and the National Cancer Institute (R01 CA102278).
Conflict-of-interest disclosure: The authors declare no competing financial interests. ■
- © 2009 by The American Society of Hematology