Inhibition of human brain tumor cell growth by the anti-inflammatory drug, flurbiprofen.
Despite many efforts to alter the relentlessly aggressive progression of tumors of neural origin, individuals bearing these tumors exhibit poor prognosis for long-term survival. In an attempt to find an effective treatment, we examined the efficacy of the non-steroidal anti-inflammatory drug, flurbiprofen, to suppress the growth of tumor cell lines derived from medulloblastoma and glioblastoma multiforme. Results from cell proliferation assays have revealed that flurbiprofen effectively inhibits the growth of various tumor cells in a dose-dependent manner and causes a noticeable change in the progression of cells through cell cycle stages. Treatment of tumor cells with flurbiprofen reduced the number of cells in G1 and G2, and significantly increased their numbers in S phase, suggesting that, flurbiprofen accelerates G1/S entry, and/or delays cell exit from S to G2/M stages. Results from RNase protection assay and Western blot analysis showed that while treatment of cells with flurbiprofen causes a minor change in the RNA level of different cyclins, there is a significant decrease in the level of cyclin B protein upon flurbiprofen treatment. Examination of tumor suppressors by RNase protection technique showed a subtle increase in the levels of several tumor suppressors upon flurbiprofen treatment. Interestingly, at the protein level, p53 tumor suppressor was substantially increased upon flurbiprofen treatment, yet the level of p21, a downstream target for p53 remained unchanged. Curiously, treatment of the cells with flurbiprofen enhanced the level of COX-2 expression. Results from co-immunoprecipitation showed association of COX-2 with p53 in tumor cells. These observations suggest that the interaction of COX-2 with p53 may cause p21-independent suppression of tumor cell growth upon flurbiprofen treatment.
King
J G
JG
Laboratory of Cancer Biology and Intervention, Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, PA 19122, USA.
Khalili
K
K
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D019926:Cyclin B / Q000096:biosynthesis / Q000235:genetics; D051546:Cyclooxygenase 2; D005480:Flurbiprofen / Q000494:pharmacology*; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008527:Medulloblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D019926:Cyclin B; D007527:Isoenzymes; D008565:Membrane Proteins; D012334:RNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D005480:Flurbiprofen; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases