Abstract 4539: Nitroxide-aspirin conjugates: A new class of NSAIDs

Novel nitroxide-aspirin conjugates were synthesized and tested using human lung cancer cell lines. Previously, cyclooxygenase (COX2) was found to be elevated in lung cancer biopsy specimens relative to normal tissue (He et al., 2012; PlosOne 7:e31087). Lung cancer cellular proliferation is inhibited by nonsteroidal anti-inflamatory drugs (NSAIDs) such as indomethacin and aspirin (Hida et al., 1998; Anticancer Res. 18: 775). Dithiolethione-valproate conjugates inhibit COX-2 activity, increase E-cadherin expression and decrease the proliferation of non-small cell lung cancer (NSCLC) cells (Moody et al., 2010, Lung Cancer 68: 154). Here the effects of nitroxide-aspirin conjugates were investigated on NSCLC cells. 1KT121A, a 4-carboxy Tempo-aspirin conjugate, inhibited the proliferation of NCI-H1299 or A549 cells with IC50 values of 125 uM using the MTT assay whereas aspirin and tempol had IC50 values of 750 and >1000 uM, respectively. 1KT121A, which has an ester link, was approximately 5-fold more potent at inhibiting NSCLC cellular proliferation than aspirin plus tempol or 2KT106A, which is a Tempo-aspirin conjugate with an amide link. 1KT121A was more potent than 2KT106A or tempol plus aspirin at reducing prostaglandin E2 levels in A549 cells. Similar results were obtained if the nitroxide moiety was changed from 4-carboxy Tempo to 3-carboxy proxyl or 5-carboxy-1,1,3,3-tetramethylisoindolin-yloxyl (CTMIO). 1KT121A potentiated the ability of gefitinib, an EGF receptor tyrosine kinase inhibitor, to kill NSCLC cells. Because 1KT121A increased E-cadherin and reduced vimentin, it may impair epithelial-mesenchymal transitions of NSCLC cells. All of the nitoxide analogues were antioxidants based on the ability to inhibit reactive oxygen species in NSCLC cells treated with hydrogen peroxide. Nitroxide-aspirin conjugates represent a novel class of NSAIDs which are antioxidants that inhibit NSCLC proliferation. Citation Format: Terry W. Moody, Robert T. Jensen, Komba Thomas, Kathryn E. Fairfull-Smith, Steven E. Bottle, Lisa Ridnour, David A. Wink. Nitroxide-aspirin conjugates: A new class of NSAIDs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4539. doi:10.1158/1538-7445.AM2015-4539