Nitroxide derivatives of non‐steroidal anti‐inflammatory drugs exert anti‐inflammatory and superoxide dismutase scavenging properties in A459 cells

• Published in: British journal of pharmacology Vol. 165; no. 4b; pp. 1058 - 1067
• Main Authors: Flores‐Santana, Wilmarie, Moody, Terry, Chen, Weibin, Gorczynski, Michael J, Shoman, Mai E, Velázquez, Carlos, Thetford, Angela, Mitchell, James B, Cherukuri, Murali K, King, S Bruce, Wink, David A
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.02.2012
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - toxicity; antioxidants; Antioxidants - chemistry; Antioxidants - pharmacology; Antioxidants - toxicity; Aspirin - chemistry; Aspirin - pharmacology; Aspirin - toxicity; cancer; Carrageenan; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cyclic N-Oxides - chemistry; Cyclic N-Oxides - pharmacology; Cyclic N-Oxides - toxicity; Dinoprostone - metabolism; Disease Models, Animal; Edema - chemically induced; Edema - drug therapy; Female; Humans; Indomethacin - chemistry; Indomethacin - pharmacology; Indomethacin - toxicity; inflammation; Leukotriene B4 - metabolism; Mice; Mice, Nude; nitrosative stress; nitroxides; NSAIDS; Rats; Research Papers; Stomach Ulcer - chemically induced; Stomach Ulcer - drug therapy; Superoxide Dismutase - metabolism
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2011.01527.x

BACKGROUND AND PURPOSE Inflammation and reactive oxygen species are associated with the promotion of various cancers. The use of non‐steroidal anti‐inflammatory drugs (NSAIDs) in cancer prevention treatments has been promising in numerous cancers. We report the evaluation of NSAIDs chemically modified by the addition of a redox‐active nitroxide group. TEMPO‐aspirin (TEMPO‐ASA) and TEMPO‐indomethacin (TEMPO‐IND) were synthesized and evaluated in the lung cancer cell line A549. EXPERIMENTAL APPROACHES We evaluated physico‐chemical properties of TEMPO‐ASA and TEMPO‐IND by electron paramagnetic resonance and cyclic voltammetry. Superoxide dismutase‐like properties was assayed by measuring cytochrome c reduction and anti‐inflammatory effects were assayed by measuring production of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). MTT proliferation assay and clonogenic assay were evaluated in the A549 lung carcinoma cell line. Maximum tolerated doses (MTD) and acute ulcerogenic index were also evaluated in in vivo. KEY RESULTS MTD were: TEMPO (140 mg·kg−1), ASA (100 mg·kg−1), indomethacin (5 mg·kg−1), TEMPO‐ASA (100 mg·kg−1) and TEMPO‐IND (40 mg·kg−1). While TEMPO‐ASA was as well tolerated as ASA, TEMPO‐IND showed an eightfold improvement over indomethacin. TEMPO‐IND showed markedly less gastric toxicity than the parent NSAID. Both TEMPO‐ASA and TEMPO‐IND inhibited production of PGE2 and LTB4 in A549 cells with maximum effects at 100 µg·mL−1 or 10 µg·mL−1 respectively. CONCLUSIONS AND IMPLICATIONS The nitroxide‐NSAIDs retained superoxide scavenging capacity of the parent nitroxide and anti‐inflammatory effects, inhibiting cyclooxygenase and 5‐lipoxygenase enzymes. These redox‐modified NSAIDs might be potential drug candidates, as they exhibit the pharmacological properties of the parent NSAID with antioxidant activity decreasing NSAID‐associated toxicity.