Faculty of Pharmacy, The University of Sydney, New South Wales, Australia.
Nutr Cancer. 2011;63(3):435-43. doi: 10.1080/01635581.2011.535959.
Flavonoids are components of plant foods and of many herbal medicines taken in combination with anticancer drugs. We have examined the potential of flavonoids to affect the accumulation and cytotoxicity of 3 cytotoxic drugs [vinblastine (VLB), daunorubicin (DNR), and colchicine (COL)] that are substrates for the ABC transporter, P-glycoprotein in a vinblastine-resistant T-cell leukemia, CEM/VBL(100), that overexpresses P-glycoprotein. The effects of the flavonoids on accumulation and cytotoxicity of these drugs were different depending on the P-gp substrate used. Most of the 30 flavonoids tested decreased DNR accumulation in the VBL-resistant, but not sensitive, leukemia cells. By contrast, flavonoids that inhibited DNR accumulation enhanced the accumulation of fluorescently labeled vinblastine. None of these flavonoids affected COL accumulation. The effects of the flavonoids on the cytotoxicities of these drugs paralleled their effects on accumulation; the same flavonoids decreased DNR cytotoxicity but increased VLB cytotoxicity and had no effect on COL. Verapamil reversed the accumulation deficit and cytotoxicity of all three P-gp substrates. These effects correlated with the effects of flavonoids on P-gp-ATPase activity. Flavonoids that decreased DNR accumulation stimulated DNR-activated P-gp ATPase, whereas flavonoids that increased fluorescently labeled VLB accumulation inhibited VBL-stimulated P-gp ATPase activity, thereby accounting for the decrease or increase in cancer drug accumulation in resistant cells. We conclude that flavonoids often ingested by cancer patients may have different effects on anticancer drugs and that these findings should be considered in designing future combination treatments for cancer patients.
类黄酮是植物性食物和许多中草药的成分，与抗癌药物联合使用。我们研究了类黄酮对 ABC 转运蛋白 P-糖蛋白底物[长春碱 (VLB)、柔红霉素 (DNR)和秋水仙碱 (COL)]在过表达 P-糖蛋白的长春碱耐药 T 细胞白血病 CEM/VBL(100)中的积累和细胞毒性的潜在影响。类黄酮对这些药物积累和细胞毒性的影响因 P-gp 底物的不同而不同。在用 30 种类黄酮进行测试的大多数情况下，DNR 在 VLB 耐药而不是敏感的白血病细胞中的积累减少。相比之下，抑制 DNR 积累的类黄酮增强了荧光标记的长春碱的积累。这些类黄酮都没有影响 COL 的积累。类黄酮对这些药物细胞毒性的影响与其对积累的影响相似；相同的类黄酮降低了 DNR 的细胞毒性，但增加了 VLB 的细胞毒性，对 COL 没有影响。维拉帕米逆转了所有三种 P-gp 底物的积累不足和细胞毒性。这些作用与类黄酮对 P-gp-ATP 酶活性的影响相关。减少 DNR 积累的类黄酮刺激 DNR 激活的 P-gp ATP 酶，而增加荧光标记 VLB 积累的类黄酮抑制 VLB 刺激的 P-gp ATP 酶活性，从而解释了耐药细胞中抗癌药物积累的减少或增加。我们得出结论，癌症患者经常摄入的类黄酮可能对抗癌药物有不同的影响，在为癌症患者设计未来的联合治疗方案时应考虑到这些发现。
