Characterizing Nitro-Fatty Acids as Rad51 Inhibitors and Cotreatment in Triple-Negative Breast Cancer
Abstract
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 is identically equal to CH) terminus on OA-NO2 facilitates secondary "click" reactions with azido-substituted affinity tags that facilitate protein pull-down as well as HPLC-MS/MS-based detection. Preliminary studies support click chemistry-based Rad51 and Beta-actin pulldown through alkynyl-tagged NFAs from cell lysate.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2020
- Accession Number
- AD1101257
Entities
People
- Bruce A. Freeman
- Carola A. Neumann
Organizations
- University of Pittsburgh