We assessed the relationship between oxidative stress, cytokinetic parameters and tumor growth in response to the novel phospho-NSAIDs, agents with significant anticancer effects in preclinical models. Compared to controls, in SW480 colon and MCF-7 breast cancer cells, phospho-sulindac, phospho-aspirin, phospho-flurbiprofen, and phospho-ibuprofen (P-I) increased the levels of reactive oxygen and nitrogen species (RONS) and decreased glutathione levels and thioredoxin reductase activity, whereas the conventional chemotherapeutic drugs (CCDs) 5-fluorouracil (5-FU), irinotecan, oxaliplatin, chlorambucil, taxol and vincristine did not. In both cell lines, phospho-NSAIDs induced apoptosis and inhibited cell proliferation much more potently than CCDs. We then treated nude mice bearing SW480 xenografts with P-I or 5-FU that had opposite effect on RONS in vitro. Compared to controls, P-I markedly suppressed xenograft growth, induced apoptosis in the xenografts (8.9±2.7 vs. 19.5±3.0), inhibited cell proliferation (52.6±5.58 vs. 25.8±7.71) and increased urinary F2-isoprostane levels (10.7±3.3 vs. 17.9±2.2 ng/mg creatinine), a marker of oxidative stress; all differences were statistically significant. 5-FU's effects on tumor growth, apoptosis, proliferation and F2-isoprostane were not statistically significant. F2-isoprostane levels correlated with the induction of apoptosis and the inhibition of cell growth. P-I induced oxidative stress only in the tumors and its apoptotic effect was restricted to xenografts. Our data show that phospho-NSAIDs act against cancer through a mechanism distinct from that of various CCDs; underscore the critical role of oxidative stress in their effect; and indicate that pathways leading to oxidative stress may be useful targets for anticancer strategies.
- Received May 9, 2011.
- Revision received June 2, 2011.
- Accepted June 3, 2011.
- The American Society for Pharmacology and Experimental Therapeutics