title: Selectively enhanced radiation sensitivity in prostate cancer cells associated with proteasome inhibition.
abstract: The purpose of this study is to evaluate the utility of MG-132, a broad spectrum proteasome inhibitor, to selectively enhance radiation sensitivity in prostate cancer without affecting normal surrounding urothelial tissue. PC3 prostate cancer cells and normal URO-tsa bladder epithelial cells were treated with or without MG-132 and exposed to 0, 2, 4, or 6 Gy radiation. Cell viability and clonogenic survival assays were performed, and nuclear factor kappa-B (NF-kappaB) activity was evaluated with electrophoretic mobility shift assay (EMSA). MG-132 was associated with decreased cell viability (between 24% and 33%) and clonogenic survival (between 71% and 88%) alone and in combination with radiation in PC3 cells. MG-132 had no effect on cell viability or clonogenic survival following radiation in URO-tsa cells. Constitutive and radiation-induced NF-kappaB binding activity was higher in PC3 cells compared with URO-tsa cells. Furthermore, MG-132 at concentrations associated with reductions in cell viability and clongenic survival inhibited NF-kappaB binding activity in PC3 cells with no effect in URO-tsa cells. These results provide strong evidence that proteasome inhibition and concomitant NF-kappaB inhibition can be used to selectively enhance tumor radiation sensitivity in prostate cancer without affecting normal surrounding bladder tissue.
authors.affiliation: Department of Radiation Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Graham
authors.initials: G
authors.lastname: Warren
authors.forename: Kris
authors.initials: K
authors.lastname: Grimes
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Mahesh
authors.initials: M
authors.lastname: Kudrimoti
authors.forename: William
authors.initials: W
authors.lastname: St Clair
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D003114:Colony-Forming Units Assay; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D061988:Proteasome Inhibitors; D011836:Radiation Tolerance / Q000187:drug effects / Q000502:physiology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011838:Radiation-Sensitizing Agents; D051550:I-kappa B Kinase; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde