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

作者：Flores Santana Wilmarie; Moody Terry; Chen Weibin; Gorczynski Michael J; Shoman Mai E; Velazquez Carlos; Thetford Angela; Mitchell James B; Cherukuri Murali K; King S Bruce; Wink David A^*

来源：British Journal of Pharmacology, 2012, 165(4B): 1058-1067.

DOI：10.1111/j.1476-5381.2011.01527.x

• NSAIDS
• nitroxides
• cancer
• nitrosative stress
• inflammation
• antioxidants

BACKGROUND AND PURPOSE %26lt;br%26gt;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. %26lt;br%26gt;EXPERIMENTAL APPROACHES %26lt;br%26gt;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 E-2 (PGE(2)) and leukotriene B-4 (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. %26lt;br%26gt;KEY RESULTS %26lt;br%26gt;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 PGE(2) and LTB4 in A549 cells with maximum effects at 100 mg.mL(-1) or 10 mg.mL(-1) respectively. %26lt;br%26gt;CONCLUSIONS AND IMPLICATIONS %26lt;br%26gt;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.

• 出版日期2012-2