The
sodium iodide symporter (NIS) mediates the active
iodide uptake in the thyroid gland as well as lactating breast tissue. Recently, we reported significant stimulation of
all-trans retinoic acid (atRA)-induced NIS expression in the
estrogen-receptor positive human
breast cancer cell line MCF-7 by
dexamethasone (Dex) in vitro and in vivo, which might offer the potential to image and treat
breast cancer with radioiodine. In this study, based on its known interaction with the
pregnane-X-receptor (PXR) forming a heterodimer with the
retinoid-X-receptor (RXR), we examined the effect of
carbamazepine (CBZ), a potent activator of PXR, on atRA-induced NIS expression and therapeutic efficacy of (131)I in MCF-7 cells. For this purpose, functional NIS expression in MCF-7 cells was examined by
iodide uptake assay, quantitative real-time PCR as well as Western blot analysis, followed by investigation of (131)I cytotoxicity in vitro after incubation with CBZ (4, 25, 100 μM) in the presence of atRA (1 μM) with or without Dex (100 nM). Incubation with CBZ stimulated atRA-induced
iodide accumulation up to twofold in a concentration-dependent manner, while atRA/Dex-stimulated
iodide uptake was further stimulated up to 1.5-fold by additional CBZ treatment based on significantly increased NIS
mRNA and
protein levels. This stimulatory effect of CBZ was shown to be dependent on the PI3K-Akt pathway without involvement of mTOR. In contrast, treatment with CBZ alone had no effect on functional NIS expression. Moreover, selective cytotoxicity of (131)I was significantly increased from approximately 20% in MCF-7 cells treated with atRA alone to 50%
after treatment with CBZ in the presence of atRA, which was further enhanced to 90% after combined treatment with atRA/Dex/CBZ. In conclusion, CBZ represents another potent stimulator of atRA-induced functional NIS expression resulting in an enhanced selective killing effect of (131)I in MCF-7
breast cancer cells.