A comparison of the effectiveness of selected non-steroidal anti-inflammatory drugs and their derivatives against cancer cells in vitro.
OBJECTIVE
Previously, we reported in vitro observations suggesting that ibuprofen is an effective non-prescription non-steroidal anti-inflammatory drug (NSAID) to reduce the survival of human prostate cancer cells (Andrews et al. in Cancer Chemother Pharmacol 502:77-284, 2002), and that this observed effectiveness is mediated by an up-regulation of the p75 NTR tumor suppressor (Khwaja et al. in Cancer Res 646:207-6213, 2004). However, other NSAIDs and their derivatives have received significant attention with regard to their anti-cancer effectiveness and have been selected for clinical trials to treat a variety of human cancers. In this investigation, we compared celecoxib, sulindac sulfone, nitric oxide linked NSAIDs, and R-flurbiprofen with ibuprofen in their ability to inhibit the growth of a variety of human cancer cells lines including cells lines with multi-drug resistance. We also evaluated whether, like ibuprofen, an up-regulation of p75 NTR is a molecular mechanism that mediates the anti-growth effectiveness of these drugs.


METHODS
Selected dosages for each drug were evaluated for their ability to reduce the growth (MTT analysis) and induce apoptosis (Hoechst staining) of a variety of different cancer cell lines, including an ovarian cell line expressing multidrug resistance-1 glycoprotein (MDR-1). The drugs were then analyzed using immunoblot, RT-PCR and siRNA to study the role of p75 NTR in their anti-growth effectiveness.


RESULTS
Our study revealed consistency in the drug dosages that inhibit the survival of different human cancer cell lines. While NO-linked aspirin and celecoxib were most effective in decreasing cell growth and inducing apoptosis at the lowest dosages, R-flurbiprofen and ibuprofen were most effective at clinically relevant dosages. A multidrug resistant ovarian cell line is more resistant to growth inhibition by the drugs tested than its non-drug resistant parental counterpart. There was no correlation between the expression of cyclooxygenase-2 (COX-2) and the ability of the drugs to reduce cancer cell survival. All the drugs tested induced an up-regulation in p75 NTR tumor suppressor gene expression in concert with their observed growth inhibiting ability. Inhibition of p75 NTR expression with siRNA reduced the cell growth inhibiting effects of all the drugs tested.


CONCLUSIONS
The method of chemotherapy (i.e., intravascular, intrathecal, oral) might dictate the choice of NSAID/NSAID derivative used to treat/prevent a given type of cancer. Also, the p75 NTR tumor suppressor appears to be a common molecular mechanism that mediates the growth inhibiting effectiveness of these drugs.
Andrews
Peter
P
Department of Cell Biology, Georgetown University School of Medicine, 3900 Reservoir Road, NW, Washington, DC 20007, USA. andrewsp@georgetown.edu
Zhao
Xu
X
Allen
Jeffrey
J
Li
Fengmin
F
Chang
Melissa
M
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012334:RNA, Neoplasm / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D020800:Receptor, Nerve Growth Factor / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D020800:Receptor, Nerve Growth Factor; D051546:Cyclooxygenase 2