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PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line
Stefan Harmsen1, I Meijerman, C L Febus
1Division of Biomedical Analysis, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Sorbonnelaan 16, Utrecht, The Netherlands. s.harmsen@uu.nl
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.
Insights
Several anticancer drugs activate P-glycoprotein (Pgp) induction via the pregnane X receptor (PXR), contributing to multidrug resistance (MDR) in cancer treatment. This finding impacts chemotherapy efficacy and drug resistance mechanisms.
Area of Science:
- Pharmacology
- Oncology
- Molecular Biology
Background:
- Multidrug resistance (MDR) significantly limits cancer treatment efficacy.
- P-glycoprotein (Pgp) induction is a key mechanism driving anticancer drug-induced MDR.
- The pregnane X receptor (PXR) plays a role in regulating Pgp induction.
Purpose of the Study:
- To investigate the ability of common anticancer drugs to activate PXR-mediated Pgp induction.
- To understand the role of PXR in anticancer drug-induced Pgp expression.
- To assess the impact of these drugs on Pgp substrate accumulation.
Main Methods:
- Pgp-reporter gene assay to evaluate drug-induced Pgp.
- Pgp protein expression analysis in wild-type and PXR-knocked down cells.
- Intracellular accumulation studies using Pgp probes (rhodamine 123, doxorubicin).
Main Results:
- Vincristine, tamoxifen, vinblastine, docetaxel, cyclophosphamide, flutamide, ifosfamide, and paclitaxel were found to activate PXR-mediated Pgp induction.
- These drugs affected the intracellular accumulation of rhodamine 123.
- PXR activation reduced the cytotoxic effect of doxorubicin in colon cancer cells.
Conclusions:
- Multiple anticancer drugs activate PXR, leading to Pgp induction.
- This activation influences the accumulation of Pgp substrates.
- Understanding these mechanisms is crucial for overcoming MDR in cancer therapy.
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