Modulation of P-glycoprotein-Mediated Anticancer Drug Accumulation, Cytotoxicity, and ATPase Activity by Flavonoid Interactions
Modulation of P-glycoprotein-Mediated Anticancer Drug Accumulation, Cytotoxicity, and ATPase Activity by Flavonoid Interactions
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DOI：
10.1080/01635581.2011.535959
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发表时间：
2011-01-01
影响因子：
2.9
通讯作者：
Roufogalis, Basil D.
中科院分区：
文献类型：
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作者：
Tran, Van H.;Marks, Denese;Roufogalis, Basil D.
黄酮类化合物是植物性食物和许多与抗癌药物联合服用的草药的成分。我们研究了类黄酮对3种细胞毒性药物[长春碱（VLB）、柔红霉素（DNR）和秋水仙碱（COL）]的蓄积和细胞毒性的影响，这些药物是ABC转运蛋白的底物，在长春碱耐药T细胞白血病CEM/VBL 100中，P-糖蛋白过度表达。这些药物的积累和细胞毒性的黄酮类化合物的影响是不同的，这取决于所使用的P-gp底物。测试的30种黄酮类化合物中的大多数降低了VBL抗性白血病细胞中DNR的积累，但不敏感。相反，抑制柔红霉素积累的黄酮类化合物增强了荧光标记的长春碱的积累。这些黄酮类化合物都不影响COL的积累。黄酮类化合物对这些药物的细胞毒性的影响，其影响的积累;相同的黄酮类化合物降低DNR细胞毒性，但增加VLB细胞毒性，并没有对COL的影响。维拉帕米逆转的积累赤字和细胞毒性的所有三个P-gp底物。这些作用与黄酮类化合物对P-gp-ATPase活性的影响有关。降低DNR积累的黄酮类化合物刺激DNR激活的P-gp ATP酶，而增加荧光标记的VLB积累的黄酮类化合物抑制VBL刺激的P-gp ATP酶活性，从而解释耐药细胞中癌症药物积累的减少或增加。我们的结论是，黄酮类化合物经常摄入的癌症患者可能有不同的抗癌药物的影响，这些研究结果应考虑在设计未来的联合治疗癌症患者。
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/VBL100, 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.