Hooijberg J H, Broxterman H J, Scheffer G L, Vrasdonk C, Heijn M, de Jong M C, Scheper R J, Lankelma J, Pinedo H M
Department of Medical Oncology, Academisch Ziekenhuis Vrije Universiteit, Amsterdam, The Netherlands.
Br J Cancer. 1999 Sep;81(2):269-76. doi: 10.1038/sj.bjc.6690687.
The multidrug resistance protein 1 (MRP1) is an ATP-dependent transport protein for organic anions, as well as neutral or positively charged anticancer agents. In this study we show that flavopiridol, a synthetic flavonoid currently studied in phase 1 trials for its antiproliferative characteristics, interacts with MRP1 in a potent way. Flavopiridol, as well as other (iso)flavonoids stimulate the ATPase activity of MRP1 in a dose-dependent way at low micromolar concentrations. A new specific monoclonal antibody against MRP1 (MIB6) inhibits the (iso)flavonoid-induced ATPase activity of plasma membrane vesicles prepared from the MRP1 overexpressing cell line GLC4/ADR. The accumulation of daunorubicin in GLC4/ADR cells is increased by flavopiridol and by other non-glycosylated (iso)flavonoids that interact with MRP1 ATPase activity. However, flavopiridol is the only tested compound that affects the daunorubicin accumulation when present at concentrations below 1 microM. Glycosylated (iso)flavonoids do not affect MRP1-mediated transport or ATPase activity. Finally, MRP1 overexpressing and transfected cells are resistant to flavopiridol, but not to other (iso)flavonoids tested. These findings may be of relevance for the development of anticancer therapies with flavopiridol.
多药耐药蛋白1（MRP1）是一种依赖ATP的有机阴离子转运蛋白，也是中性或带正电荷的抗癌药物转运蛋白。在本研究中，我们发现，目前正在1期试验中因其抗增殖特性而被研究的合成类黄酮黄酮哌啶醇，能以强效方式与MRP1相互作用。黄酮哌啶醇以及其他（异）黄酮在低微摩尔浓度下以剂量依赖方式刺激MRP1的ATP酶活性。一种新的针对MRP1的特异性单克隆抗体（MIB6）抑制从过表达MRP1的细胞系GLC4/ADR制备的质膜囊泡的（异）黄酮诱导的ATP酶活性。柔红霉素在GLC4/ADR细胞中的蓄积因黄酮哌啶醇和其他与MRP1 ATP酶活性相互作用的非糖基化（异）黄酮而增加。然而，黄酮哌啶醇是唯一在浓度低于1微摩尔时影响柔红霉素蓄积的受试化合物。糖基化（异）黄酮不影响MRP1介导的转运或ATP酶活性。最后，过表达和转染MRP1的细胞对黄酮哌啶醇耐药，但对其他受试（异）黄酮不耐药。这些发现可能与黄酮哌啶醇抗癌治疗的开发相关。
