학술논문
Small molecule nitroalkenes inhibit RAD51-mediated homologous recombination and amplify triple-negative breast cancer cell killing by DNA-directed therapies.
Document Type
Academic Journal
Author
Hong L; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women's Research Institute, Pittsburgh, PA, USA.; Braden DC; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women's Research Institute, Pittsburgh, PA, USA.; Zhao Y; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women's Research Institute, Pittsburgh, PA, USA; School of Medicine, Tsinghua University, Beijing, China.; Skoko JJ; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women's Research Institute, Pittsburgh, PA, USA.; Chang F; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.; Woodcock SR; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.; Uvalle C; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.; Casey A; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women's Research Institute, Pittsburgh, PA, USA.; Wood K; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.; Salvatore SR; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.; Asan A; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women's Research Institute, Pittsburgh, PA, USA.; Harkness T; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women's Research Institute, Pittsburgh, PA, USA.; Fagunloye A; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women's Research Institute, Pittsburgh, PA, USA.; Razzaghi M; Department of Biochemistry and Molecular Biology, University of Iowa, Iowa City, IA, USA.; Straub A; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.; Spies M; Department of Biochemistry and Molecular Biology, University of Iowa, Iowa City, IA, USA.; Brown DD; Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Lee AV; Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Schopfer F; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.; Freeman BA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.; Neumann CA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women's Research Institute, Pittsburgh, PA, USA. Electronic address: neumannc@upmc.edu.
Source
Publisher: Elsevier, B.V Country of Publication: Netherlands NLM ID: 101605639 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2213-2317 (Electronic) Linking ISSN: 22132317 NLM ISO Abbreviation: Redox Biol Subsets: MEDLINE
Subject
Language
English
Abstract
Nitro fatty acids (NO 2 -FAs) are endogenously generated lipid signaling mediators from metabolic and inflammatory reactions between conjugated diene fatty acids and nitric oxide or nitrite-derived reactive species. NO 2 -FAs undergo reversible Michael addition with hyperreactive protein cysteine thiolates to induce posttranslational protein modifications that can impact protein function. Herein, we report a novel mechanism of action of natural and non-natural nitroalkenes structurally similar to (E) 10-nitro-octadec-9-enoic acid (CP-6), recently de-risked by preclinical Investigational New Drug-enabling studies and Phase 1 and Phase 2 clinical trials and found to induce DNA damage in a TNBC xenograft by inhibiting homologous-recombination (HR)-mediated repair of DNA double-strand breaks (DSB). CP-6 specifically targets Cys319, essential in RAD51-controlled HR-mediated DNA DSB repair in cells. A nitroalkene library screen identified two structurally different nitroalkenes, a non-natural fatty acid [(E) 8-nitro-nonadec-7-enoic acid (CP-8)] and a dicarboxylate ester [dimethyl (E)nitro-oct-4-enedioate (CP-23)] superior to CP-6 in TNBC cells killing, synergism with three different inhibitors of the poly ADP-ribose polymerase (PARP) and γ-IR. CP-8 and CP-23 effectively inhibited γ-IR-induced RAD51 foci formation and HR in a GFP-reported assay but did not affect benign human epithelial cells or cell cycle phases. In vivo, CP-8 and CP-23's efficacies diverged as only CP-8 showed promising anticancer activities alone and combined with the PARP inhibitor talazoparib in an HR-proficient TNBC mouse model. As preliminary preclinical toxicology analysis also suggests CP-8 as safe, our data endorse CP-8 as a novel anticancer molecule for treating cancers sensitive to homologous recombination-mediated DNA repair inhibitors.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)