THE SPECIFIC BISINDOLYLMALEIMIDE PKC-INHIBITOR GF 109203X EFFICIENTLY MODULATES MRP-ASSOCIATED MULTIPLE-DRUG RESISTANCE
THE SPECIFIC BISINDOLYLMALEIMIDE PKC-INHIBITOR GF 109203X EFFICIENTLY MODULATES MRP-ASSOCIATED MULTIPLE-DRUG RESISTANCE
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DOI：
10.1006/bbrc.1995.1017
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发表时间：
1995-01-05
影响因子：
3.1
通讯作者：
BECK, J
中科院分区：
文献类型：
--
作者：
GEKELER, V;BOER, R;BECK, J
新发现的药物转运蛋白 MRP 在功能上与独立于 P-糖蛋白的多重耐药性有关。目前针对此类 MDR 的耐药调节剂很少见。我们分析了高选择性双吲哚马来酰亚胺 PKC 抑制剂 GF 109203X 对 MRP 过表达的人 MDR 亚系 HL60/AR 和 GLC4/ADR 的调节作用。应用 72 小时 MTT 测定，我们证明 HL60/AR 细胞的长春新碱耐药性完全逆转。 HL60/AR的阿霉素耐药性或GLC4/ADR的长春新碱耐药性被部分逆转。此外，来自 HL60/AR 的罗丹明 123 流出受到 GF 109203X 的强烈调节。由于 PKC 抑制剂在 mRNA 水平上没有显着影响 MRP 基因表达（通过 cDNA-PCR 检测），因此我们的结果表明该化合物与 MRP 直接相互作用或/和通过改变转运蛋白的磷酸化状态间接影响 MRP 活性。 (C) 1995 学术出版社
The newly identified drug transporter MRP is functionally linked to a multiple drug resistance independent from P-glycoprotein. Resistance modifiers for this type of MDR are rare at present. We analyzed the modulating effect of the highly selective bisindolylmaleimide PKC inhibitor GF 109203X on the MRP overexpressing human MDR sublines HL60/AR and GLC4/ADR. Applying a 72 hour MTT-assay we demonstrate a complete reversal of the vincristine resistance of HL60/AR cells. Adriamycin resistance of HL60/AR, or vincristine resistance of GLC4/ADR were partially reversed. Furthermore, rhodamine 123 efflux from HL60/AR was strongly modulated by GF 109203X. Since the PKC inhibitor did not significantly influence MRP gene expression at the mRNA level which was examined by cDNA-PCR, our results suggest either a direct interaction of the compound with MRP or/and an indirect influence on MRP activity via altering the phosphorylation status of the transporter. (C) 1995 Academic Press, Inc.