Because
cancer is often treated with combination
therapy, unexpected pharmacological effects can occur because of
drug-drug interactions. Several drugs are able to cause upregulation or downregulation of
drug transporters or
cytochrome P450 enzymes, particularly
CYP3A4. Induction of
CYP3A4 may result in decreased plasma levels and therapeutic efficacy of anticancer drugs. Since the
pregnane X receptor (PXR) is one of the major transcriptional regulators of
CYP3A4, PXR antagonists can possibly prevent
CYP3A4 induction. Currently, a limited number of PXR antagonists are available. Some of these antagonists, such as
sulphoraphane and
coumestrol, belong to the so-called complementary and alternative medicines (CAM). Therefore, the aim was to determine the potential of selected CAM (β-
carotene, Echinacea purpurea, garlic, Ginkgo biloba, ginseng, grape seed,
green tea, milk thistle,
saw palmetto, valerian, St. John's Wort, and
vitamins B6, B12, and C) to inhibit PXR-mediated
CYP3A4 induction at the transcriptional level, using a reporter gene assay and a real-time polymerase chain reaction assay in LS180
colon adenocarcinoma cells. Furthermore, computational molecular docking and a LanthaScreen time-resolved fluorescence resonance energy transfer (TR-FRET) PXR competitive binding assay were performed to explore whether the inhibiting CAM components interact with PXR. The results demonstrated that milk thistle is a strong inhibitor of PXR-mediated
CYP3A4 induction. The components of milk thistle responsible for this effect were identified as
silybin and
isosilybin. Furthermore, computational molecular docking revealed a strong interaction between both
silybin and
isosilybin and PXR, which was confirmed in the TR-FRET PXR assay. In conclusion,
silybin and
isosilybin might be suitable candidates to design potent PXR antagonists to prevent
drug-drug interactions via
CYP3A4 in
cancer patients.