PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line.
PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line.
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DOI：
10.1007/s00280-009-1221-4
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发表时间：
2010-09
影响因子：
3
通讯作者：
Schellens, J. H. M.
中科院分区：
文献类型：
--
作者：
Harmsen, Stefan;Meijerman, I.;Febus, C. L.;Maas-Bakker, R. F.;Beijnen, J. H.;Schellens, J. H. M.
多药耐药性（MDR）的发展是癌症治疗的主要限制之一。 P-糖蛋白（Pgp）的诱导被认为是抗癌药物诱导MDR的主要机制之一。由于 Pgp 的诱导（部分）受孕烷 X 受体 (PXR) 调节，因此研究了几种广泛使用的抗癌药物激活 PXR 介导的 Pgp 诱导的能力。采用 Pgp 报告基因测定来确定一组广泛使用的抗癌药物诱导 Pgp 的能力。为了进一步评估 PXR 是否参与抗癌药物诱导 Pgp，在野生型和 PXR 敲除的 LS180 细胞中测定了抗癌药物治疗后的 Pgp 蛋白表达。此外，还确定了抗癌药物对 Pgp 探针罗丹明 123 和阿霉素细胞内积累的影响。我们的研究表明，长春新碱、他莫昔芬、长春花碱、多西紫杉醇、环磷酰胺、氟他胺、异环磷酰胺和紫杉醇可激活 PXR 介导的 Pgp 诱导，并且还可以影响 Pgp 探针罗丹明 123 的细胞内积累。此外，PXR 激活还可以降低 Pgp 的细胞毒活性 结肠癌细胞中的底物阿霉素。我们的结果表明，几种抗癌药物可以激活 PXR 介导的 Pgp 诱导并影响 Pgp 底物的积累。
The development of multidrug resistance (MDR) is one of the major limitations in the treatment of cancer. Induction of P-glycoprotein (Pgp) has been regarded as one of the main mechanisms underlying anticancer drug-induced MDR. Since the induction of Pgp is (in part) regulated by the pregnane X receptor (PXR), the ability of several widely used anticancer drugs to activate PXR-mediated Pgp induction was investigated. A Pgp-reporter gene assay was employed to determine the ability of a panel of widely used anticancer drugs to induce Pgp. To further assess whether PXR could be involved in the induction of Pgp by anticancer drugs, Pgp protein expression after treatment with the anticancer drugs was determined in both wild-type and PXR-knocked down LS180 cells. Furthermore, the effect of the anticancer drugs on the intracellular accumulation of the Pgp-probes rhodamine 123 and doxorubicin was determined. Our study showed that vincristine, tamoxifen, vinblastine, docetaxel, cyclophosphamide, flutamide, ifosfamide and paclitaxel activate PXR-mediated Pgp induction, and were additionally shown to affect the intracellular accumulation of the Pgp probe rhodamine 123. Moreover, PXR activation was also shown to reduce the cytotoxic activity of the Pgp substrate doxorubicin in colon cancer cells. Our results indicate that several anticancer drugs can activate PXR-mediated induction of Pgp and affect the accumulation of Pgp substrates.
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影响因子：
3.3
作者：
Pfrunder, A;Gutmann, H;Drewe, J
通讯作者：
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