Dietary flavonoids inhibit the anticancer effects of the proteasome inhibitor bortezomib
Dietary flavonoids inhibit the anticancer effects of the proteasome inhibitor bortezomib
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DOI：
10.1182/blood-2008-04-150227
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发表时间：
2008-11-01
期刊：
影响因子：
20.3
通讯作者：
Jia, Li
中科院分区：
文献类型：
--
作者：
Liu, Feng-Ting;Agrawal, Samir G.;Jia, Li
膳食黄酮类化合物具有许多促进健康的作用，包括通过蛋白酶体抑制发挥抗癌活性。硼替佐米是一种二肽硼酸蛋白酶体抑制剂，具有治疗多发性骨髓瘤的活性，但对慢性淋巴细胞白血病（CLL）无效。虽然 CLL 细胞在体外培养基中培养时对硼替佐米诱导的细胞凋亡敏感，但在 50% 新鲜自体血浆中培养时，杀伤活性被阻断。膳食黄酮类化合物、槲皮素和杨梅素在血浆中含量丰富，能够以剂量依赖性方式抑制硼替佐米诱导的原发性 CLL 和恶性 B 细胞系的凋亡。这种抑制作用与硼替佐米中槲皮素和硼酸基团 -RB(OH)(2) 之间的化学反应有关。添加硼酸减弱了槲皮素和血浆对硼替佐米诱导的细胞凋亡的抑制作用。当骨髓瘤细胞系（而非 B 细胞系）与槲皮素一起预孵育时，保护作用也会降低，表明槲皮素对骨髓瘤细胞有直接作用。高剂量时，槲皮素本身会诱导肿瘤细胞死亡。这些数据表明，饮食中的类黄酮限制了硼替佐米的功效，而补充无机硼酸则能够逆转这种情况。槲皮素、肿瘤细胞和硼替佐米之间复杂的相互作用意味着在向患者提供饮食建议时需要谨慎。 （血。2008；112：3835-3846）
Dietary flavonoids have many health-promoting 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. Dietary flavonoids, quercetin and myricetin, which are abundant in plasma, inhibited bortezomib-induced apoptosis of primary CLL and malignant B-cell lines in a dose-dependent manner. This inhibitory effect was associated with chemical reactions between quercetin and the boronic acid group, -RB(OH)(2), in bortezomib. The addition of boric acid diminished the inhibitory effect of both quercetin and plasma on bortezomib-induced apoptosis. The protective effect was also reduced when myeloma cell lines, but not B-cell lines, were preincubated with quercetin, indicating a direct effect of quercetin on myeloma cells. At high doses, quercetin itself induced tumor cell death. These data indicate that dietary flavonoids limit the efficacy of bortezomib, whereas supplemental inorganic boric acid is able to reverse this. The complex interactions between quercetin, tumor cells, and bortezomib mean caution is required when giving dietary advice to patients. (Blood. 2008; 112:3835-3846)