Characterizing Nitro-Fatty Acids as Rad51 Inhibitors and Cotreatment in Triple-Negative Breast Cancer
Technical Report,01 Feb 2019,31 Jan 2020
University of Pittsburgh Pittsburgh United States
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This Research Plan is testing a readily-deployed novel drug strategy for treating TNBC, where the inhibition of Rad51-mediated DNA repair by electrophilic nitroalkenes renders TNBC cells more sensitive to PARP inhibition and TNBC cell killing. OA-NO2 and NFA-8 are nitroalkenes, 7-nitro-nonadec-7-enoic acid and 10-nitro-octadec-9-enoic acid, respectively. We have now devised an even more pharmacologically efficacious nitroalkene that shares the same active nitroalkene moiety with OA-NO2 and NFA-8, dimethyl-4-nitro-oct-4-enoiate CP-1. New data indicates that CP-1 outperforms both OA-NO2 and NFA-8, respectively. CP-1 shows not only enhanced cell killing of TNBC cells as single drugs as well as combination therapy, but also displays cell protective effects in benign breast epithelial cells that are treated with PARP inhibitors or ionizing radiation. Further, preliminary data also show that smaller alkynyl R-C equivalent CH terminus on OA-NO2 facilitates secondary click reactions with azido-substituted affinity tags that facilitate protein pull-down as well as HPLC-MSMS-based detection. Preliminary studies support click chemistry based Rad51 and beta-actin pulldown through alkynyl-tagged NFAs from cell lysate.
- Medicine and Medical Research
- Anatomy and Physiology