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

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 pregnan...

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Published in:	Cancer chemotherapy and pharmacology Vol. 66; no. 4; pp. 765 - 771
Main Authors:	Harmsen, Stefan, Meijerman, I., Febus, C. L., Maas-Bakker, R. F., Beijnen, J. H., Schellens, J. H. M.
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer-Verlag 01-09-2010 Springer Springer Nature B.V Springer Verlag
Subjects:	Adenocarcinoma - metabolism Antibiotics, Antineoplastic - metabolism Antibiotics, Antineoplastic - pharmacology Antineoplastic agents Antineoplastic Agents - pharmacology Antitubercular Agents - pharmacology ATP Binding Cassette Transporter, Subfamily B ATP Binding Cassette Transporter, Subfamily B, Member 1 - biosynthesis ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics Biological and medical sciences Blotting, Western Cancer Research Cell Line, Tumor Cell Survival - drug effects Chromatography, High Pressure Liquid Colonic Neoplasms - metabolism Doxorubicin - metabolism Doxorubicin - pharmacology Fluorescent Dyes Gastroenterology. Liver. Pancreas. Abdomen Humans Medical sciences Medicine Medicine & Public Health Oncology Original Original Article Pharmacology. Drug treatments Pharmacology/Toxicology Plasmids Pregnane X Receptor Receptors, Steroid - physiology Rhodamine 123 Rifampin - pharmacology RNA Interference Stomach. Duodenum. Small intestine. Colon. Rectum. Anus Tumors P-glycoprotein Anticancer drugs PXR Induction Multidrug resistance Antineoplastic agent Human Drug Treatment resistance Colon adenocarcinoma Pregnane X receptor P Glycoprotein Malignant tumor In vitro Colonic disease Colon cancer Multiple resistance Established cell line Digestive diseases Intestinal disease Cancer
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0344-5704 1432-0843
DOI:	10.1007/s00280-009-1221-4