Dietary flavonoids have many healthpromoting actions, including anticancer 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% fresh autologous plasma.
IntroductionBortezomib (Velcade) is a first-in-class proteasome inhibitor developed specifically for use as an antineoplastic agent. It is the most potent antineoplastic agent for the treatment of relapsed, refractory multiple myeloma. 1 A total of 73% of patients with myeloma responded to treatment with bortezomib combined with pegylated liposomal doxorubicin. 2 However, only 4 of 15 patients with acute leukemia showed a decrease in blast count. 3 The efficacy of bortezomib in chronic lymphocytic leukemia (CLL) appears to be related to IgV(H) and BCL-6 mutational status, 4 down-regulation of CD23, and inactivation of Notch 2. 5 However, we have previously shown that all primary CLL cells were sensitive to bortezomib in vitro. Proteasome inhibition increased Bax protein accumulation and Bax activation in CLL cells. Bortezomib also increased the sensitivity of CLL cells to TNF-related apoptosis-inducing ligand-induced apoptosis. 6 Although the effectiveness of bortezomib killing of CLL cells in vitro has also been reported by other groups, 4,5 it did not display substantial antitumor activity in patients with CLL. 7,8 The basis of this differential activity of bortezomib on CLL cells in vivo and in vitro is unknown. Autologous plasma is capable of maintaining survival of CLL cells in vitro and conferring resistance to chemo-radiotherapy, 9 and albumin in plasma plays an important role in this survival mechanism. 10 We sought to identify factors in the blood, which could prevent bortezomib-mediated killing of leukemic cells in the circulation.Quercetin is one of the most abundant flavonoids in the human diet and is a potent antioxidant. 11 Quercetin, abundant in human plasma, noncovalently binds to serum albumin. 12,13 It contributes to the prevention of human diseases by promoting relaxation of cardiovascular smooth muscle and protects low-density lipoprotein from oxidation. 14 Recent studies found that quercetin can induce apoptosis by inhibiting proteasome activation, 15 causing G 2 /M-phase arrest 16 and increasing p21 expression. 17 Other dietary flavonoids, such as myricetin, kaempferol, and apigenin, also have similar functions to quercetin with respect to proteasome inhibition and apoptosis induction. 15 In this study, we demonstrate that human plasma affects killing by bortezomib and that the dietary flavonoids, especially quercetin, inhibit bortezomib-induced apoptosis in malignant B-cell lines and primary CLL cells. This inhibitory activity of quercetin was associated with complex formation with bortezomib. However, in myeloma cell lines, quercetin al...