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Cancer Chemotherapy and Pharmacology

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01-02-2008 | Original Article

A comparison of the effectiveness of selected non-steroidal anti-inflammatory drugs and their derivatives against cancer cells in vitro

Authors: Peter Andrews, Xu Zhao, Jeffrey Allen, Fengmin Li, Melissa Chang

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2008

Abstract

Purpose

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.

Materials and 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^NTRin 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.

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Title: A comparison of the effectiveness of selected non-steroidal anti-inflammatory drugs and their derivatives against cancer cells in vitro
Authors: Peter Andrews
Xu Zhao
Jeffrey Allen
Fengmin Li
Melissa Chang
Publication date: 01-02-2008
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2008
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-007-0462-3

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