Oxidative Stress Mediates through Apoptosis the Anticancer Effect of Phospho-Nonsteroidal Anti-Inflammatory Drugs: Implications for the Role of Oxidative Stress in the Action of Anticancer Agents

• DOI: 10.1124/jpet.111.183533
• Publication Date: 2011-06-07T04:24:26Z
• Authors: Yu Sun; Liqun Huang; Gerardo G. Mackenzie; Basil Rigas
• Keywords: Sulindac; Flurbiprofen

We assessed the relationship between oxidative stress, cytokinetic parameters, and tumor growth in response to novel phospho-nonsteroidal anti-inflammatory drugs (NSAIDs), agents with significant anticancer effects preclinical models. Compared controls, SW480 colon MCF-7 breast cancer cells, phospho-sulindac, phospho-aspirin, phospho-flurbiprofen, phospho-ibuprofen (P-I) increased levels of reactive oxygen nitrogen species (RONS) decreased GSH thioredoxin reductase activity, whereas conventional chemotherapeutic (CCDs), 5-fluorouracil (5-FU), irinotecan, oxaliplatin, chlorambucil, paclitaxel, vincristine, did not. In both cell lines, phospho-NSAIDs induced apoptosis inhibited proliferation much more potently than CCDs. then treated nude mice bearing xenografts P-I or 5-FU that had an opposite effect on RONS vitro. markedly suppressed xenograft growth, (8.9 ± 2.7 versus 19.5 3.0), (52.6 5.58 25.8 7.71), urinary F2-isoprostane (10.7 3.3 17.9 2.2 ng/mg creatinine, a marker stress); all differences were statistically significant. 5-FU9s apoptosis, proliferation, not correlated induction inhibition growth. stress only tumors, its apoptotic was restricted xenografts. Our data show act against through mechanism distinct from various CCDs, underscore critical role their effect, indicate pathways leading may be useful targets for strategies.