Abstract
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.
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Acknowledgements
We gratefully acknowledge the contributions of Dr Reiner Class for performing FACs analysis, and Dr William J Wechter for a conversation which sparked this research. We would like to thank past and present members of the Center for Neurovirology and Cancer Biology for insightful discussion, and sharing of ideas and reagents, Dr Kris Reiss for his editorial contributions and discussions, Dr J Gordon for statistical analysis, and C Schriver for preparation of the manuscript. This work was made possible by grants awarded by NIH to K Khalili.
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King, Jr, J., Khalili, K. Inhibition of human brain tumor cell growth by the anti-inflammatory drug, flurbiprofen. Oncogene 20, 6864–6870 (2001). https://doi.org/10.1038/sj.onc.1204907
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DOI: https://doi.org/10.1038/sj.onc.1204907
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