Dexamethasone enhances the cytotoxic effect of radioiodine therapy in prostate cancer cells expressing the sodium iodide symporter.
Recently, we have reported the induction of prostate-specific radioiodine accumulation in prostate cancer cells (LNCaP) using a prostate-specific antigen (PSA)-promoter-directed expression of the sodium iodide symporter (NIS) gene. This offers the potential to treat prostate cancer with radioiodine. The aim of our current study was to examine the regulation of PSA-promoter-directed NIS expression in NIS-transfected LNCaP cells (NP-1) by dexamethasone (Dex). For this purpose, NIS mRNA and protein expression levels were examined in NP-1 cells by Northern and Western blot analysis, respectively, after incubation with Dex (10(-8)-10(-6) M) in the presence of 10(-9) M mibolerone. NIS functional activity was measured by iodide uptake assay. In addition, we examined regulation of in vitro cytotoxicity of 131-I by Dex in an in vitro clonogenic assay. After incubation with Dex, iodide accumulation in NP-1 cells increased up to 1.5-fold, whereas NIS mRNA and protein expression levels were increased up to 1.7-fold. This effect of Dex was blocked by the androgen receptor antagonist casodex (10(-6) M). The killing effect of 131-I in NP-1 cells was increased from 55% when incubated with mibolerone alone to 95% when treated with Dex (10(-7) M) plus mibolerone. Treatment of NP-1 cells with Dex resulted in an additional antiproliferative effect as measured by clonogenic assay and nonradioactive proliferation assay. In conclusion, in addition to an antiproliferative effect, treatment with Dex increases androgen-dependent NIS mRNA and protein expression as well as iodide accumulation, resulting in an increased cytotoxic effect of 131-I in prostate cancer cells stably expressing NIS under the control of the PSA-promoter.
Scholz
I V
IV
Department of Internal Medicine II, Klinikum Grosshadern, Ludwig-Maximilians-University 81377 Munich, Germany.
Cengic
N
N
Göke
B
B
Morris
J C
JC
Spitzweg
C
C
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D003907:Dexamethasone / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes / Q000494:pharmacology*; D008297:Male; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms; D012333:RNA, Messenger / Q000032:analysis; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D000099209:Sodium-Iodide Symporters
D018931:Antineoplastic Agents, Hormonal; D003907:Dexamethasone; D007457:Iodine Radioisotopes; D017430:Prostate-Specific Antigen; D012333:RNA, Messenger; D027981:Symporters; D000099209:Sodium-Iodide Symporters