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


CONCLUSIONS
Our results indicate that several anticancer drugs can activate PXR-mediated induction of Pgp and affect the accumulation of Pgp substrates.
Harmsen
Stefan
S
Division of Biomedical Analysis, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Sorbonnelaan 16, Utrecht, The Netherlands. s.harmsen@uu.nl
Meijerman
I
I
Febus
C L
CL
Maas-Bakker
R F
RF
Beijnen
J H
JH
Schellens
J H M
JH
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000230:Adenocarcinoma / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000378:metabolism*; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D005456:Fluorescent Dyes; D006801:Humans; D010957:Plasmids; D000077297:Pregnane X Receptor; D034622:RNA Interference; D011987:Receptors, Steroid / Q000502:physiology*; D020112:Rhodamine 123; D012293:Rifampin / Q000494:pharmacology
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000995:Antitubercular Agents; D005456:Fluorescent Dyes; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D020112:Rhodamine 123; D004317:Doxorubicin; D012293:Rifampin