The anticancer potency of green tea and its individual components is being intensely investigated, and some cancer patients already self-medicate with this "miracle herb" in hopes of augmenting the anticancer outcome of their chemotherapy. Bortezomib (BZM) is a proteasome inhibitor in clinical use for multiple myeloma. Here, we investigated whether the combination of these compounds would yield increased antitumor efficacy in multiple myeloma and glioblastoma cell lines in vitro and in vivo. Unexpectedly, we discovered that various green tea constituents, in particular (-)-epigallocatechin gallate (EGCG) and other polyphenols with 1,2-benzenediol moieties, effectively prevented tumor cell death induced by BZM in vitro and in vivo. This pronounced antagonistic function of EGCG was evident only with boronic acid-based proteasome inhibitors (BZM, MG-262, PS-IX), but not with several nonboronic acid proteasome inhibitors (MG-132, PS-I, nelfinavir). EGCG directly reacted with BZM and blocked its proteasome inhibitory function; as a consequence, BZM could not trigger endoplasmic reticulum stress or caspase-7 activation, and did not induce tumor cell death. Taken together, our results indicate that green tea polyphenols may have the potential to negate the therapeutic efficacy of BZM and suggest that consumption of green tea products may be contraindicated during cancer therapy with BZM. (Blood. 2009;113:5927-5937)
IntroductionHerbal supplements are commonly perceived as "innocent" or "holistic" and have become hugely popular as unrestrictedly available, over-the-counter, cure-all remedies. Cancer patients in particular may be tempted to self-medicate with such supplements in hopes to delay the progression of their disease and/or reduce the side effects associated with conventional chemotherapy, 1-3 and they may do this unbeknownst to their health care providers. 2,3 One very popular herb is green tea, brewed from the leaves of the plant Camellia sinensis, which appears to be an ideal alternative medicine because it is nontoxic and shown to have cardioprotective, neuroprotective, anti-infective, and antitumoral properties. [4][5][6][7][8][9][10] Green tea products are also available as highly concentrated extracts, which can be easily accessed by the public at local grocery, pharmacy, and health food stores throughout the United States.Green tea is a heterogeneous product that contains several antioxidant compounds, known as polyphenols. (-)-Epigallocatechin gallate (EGCG), (-)-epicatechin gallate (ECG), (-)-epigallate catechin (EGC), and (-)-epicatechin (EC) are some of the polyphenol compounds found in green tea. 9 EGCG, the most bioactive green tea polyphenol, was demonstrated to be a multipotent chemopreventive and anticancer agent in several animal models, including leukemia, lung, prostate, colon, and breast cancer. 9,[11][12][13][14][15] It was shown to interact with numerous protein targets and to disrupt biologic/biochemical reactions involved in cancer progression. The EGCG compound can vary its chemical conf...