Enhancing Effect of Radiation Therapy Using Non-Steroidal Anti-Inflammatory Agents
Abstract
Following studies with ibuprofen that demonstrated radiation sensitization with prostate cancer cells in vivo and in vitro, we are examining the potential targets of cellular radio sensitization. We observed that NSAIDs inhibited the prostaglandin synthesis at much lower concentrations than those required to induce cytotoxicity and radio sensitization, suggesting that the cellular sensitization appears to be a target other than cyclooxygenases. The mechanisms currently being explored include inhibition of NF-kB. Apoptotic pathways controlled by the Rel/NF-kB family of transcription factors may regulate the response of cells to DNA damage. In the cell lines tested, NF-kB was constitutively activated in hormone-independent PC3 and DU145 cells but was activated only by cytokine or radiation in hormone-sensitive LNCaP cells. Ibuprofen inhibited constitutive as well as stimulated NF-kB activity. We studied the activity of IKK-alpha kinase, which mediates NF-kB activation. In PC3 cells the kinase activity was constitutively active, whereas LNCaP cells had minimal kinase activity that was activated by TNF-alpha. Ibuprofen inhibited the constitutive activation of IKK-alpha kinase in PC3 cells and blocked stimulated activation of IKK-alpha kinase in LNCaP cells. The constitutive activation of NF-kB in prostate cancer cells may increase expression of anti-apoptotic proteins, thereby decreasing the effectiveness of anti-tumor therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 1999
- Accession Number
- ADA384823
Entities
People
- C. N. Coleman
Organizations
- Dana–Farber Cancer Institute