PXR 介导的抗癌药物对人结肠腺癌细胞系中 P-糖蛋白的诱导作用。

PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line.

机构信息

Division of Biomedical Analysis, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Sorbonnelaan 16, Utrecht, The Netherlands.

出版信息

Cancer Chemother Pharmacol. 2010 Sep;66(4):765-71. doi: 10.1007/s00280-009-1221-4. Epub 2009 Dec 30.

PURPOSE

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.

METHODS

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.

RESULTS

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.

CONCLUSION

Our results indicate that several anticancer drugs can activate PXR-mediated induction of Pgp and affect the accumulation of Pgp substrates.

目的

多药耐药（MDR）的发展是癌症治疗的主要限制因素之一。P-糖蛋白（Pgp）的诱导已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。

方法

采用 Pgp 报告基因测定法确定了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的 Pgp，在用抗癌药物处理后，在野生型和 PXR 敲低的 LS180 细胞中测定 Pgp 蛋白表达。此外，还测定了抗癌药物对 Pgp 探针罗丹明 123 和阿霉素的细胞内积累的影响。