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Research Articles: Therapeutics, Targets, and Development

The radiosensitization effect of parthenolide in prostate cancer cells is mediated by nuclear factor-B inhibition and enhanced by the presence of PTEN

¹ Graduate Center for Toxicology, ² Department of Radiation Medicine, and ³ College of Pharmacy, University of Kentucky, Lexington, Kentucky

Requests for reprints: William H. St. Clair, Department of Radiation Medicine, University of Kentucky, 800 Rose Street, Lexington, KY 40536. Phone: 859-323-6486; Fax: 859-257-4931. E-mail: stclair{at}uky.edu

Abstract

Parthenolide has been shown to have anti-inflammatory and antitumor properties. However, whether and how parthenolide enhances tumor sensitivity to radiation therapy are unknown. In this study, we show that inhibition of the nuclear factor-B (NF-B) pathway is a common mechanism for the radiosensitization effect of parthenolide in prostate cancer cells LNCaP, DU145, and PC3. Parthenolide inhibits radiation-induced NF-B DNA-binding activity and the expression of its downstream target sod2, the gene coding for an important antiapoptotic and antioxidant enzyme (manganese superoxide dismutase) in the three prostate cancer cells. Different susceptibilities to parthenolide's effect are observed in two radioresistant cancer cells, DU145 and PC3, with DU145 cells showing higher sensitivity. This differential susceptibility to parthenolide is due, in part, to the fact that in addition to NF-B inhibition, parthenolide activates the phosphatidylinositol-3-kinase/Akt prosurvival pathway in both cell lines. However, the activated Akt in DU145 cells is kept at a relatively low level compared with that in PC3 cells due to the presence of functional PTEN. Transfection of wild-type PTEN into PTEN-null cells, PC3, confers the enhanced radiosensitization effect of parthenolide in PTEN-expressing cells. When PTEN expression is knocked down in DU145 cells, the cells become more resistant to parthenolide's effect. Taken together, these results suggest that parthenolide inhibits the NF-B pathway and activates the phosphatidylinositol-3-kinase/Akt pathway in prostate cancer cells. The radiosensitization effect of parthenolide is due, in part, to the inhibition of the NF-B pathway. The presence of PTEN enhances the radiosensitization effect of parthenolide, in part, by suppressing the absolute amount of activated p-Akt. [Mol Cancer Ther 2007;6(9):2477–86]

Grant support: NIH grant CA49797.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/16/07; revised 6/18/07; accepted 7/10/07.