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Small molecule nitroalkenes inhibit RAD51-mediated homologous recombination and amplify triple-negative breast cancer

Lisa Hong, Dennis C Braden, Yaoning Zhao

    Biorxiv : the Preprint Server for Biology
    |August 30, 2023
    PubMed

    Insights

    Researchers identified novel nitroalkenes that kill triple-negative breast cancer (TNBC) cells by inhibiting DNA repair. CP-8 shows promise as a safe anticancer drug, especially when combined with PARP inhibitors for homologous recombination-deficient cancers.

    Area of Science:

    • Biochemistry and Molecular Biology: Investigating lipid signaling mediators and their impact on protein function.
    • Oncology: Exploring novel therapeutic strategies for triple-negative breast cancer (TNBC).
    • Genetics: Analyzing DNA double-strand break repair mechanisms, specifically homologous recombination (HR).

    Background:

    • Nitro fatty acids (NO₂-FAs) are endogenous lipid mediators involved in metabolic and inflammatory processes.
    • NO₂-FAs can modify protein function through posttranslational modifications, impacting cellular pathways.
    • Previous research identified (E)-10-nitro-octadec-9-enoic acid (CP-6) as a DNA damaging agent in TNBC xenografts by inhibiting homologous-recombination (HR) repair.

    Approach:

    • Screened a library of nitroalkenes, including natural and non-natural compounds, for enhanced TNBC cell killing activity.
    • Investigated the mechanism of action, focusing on inhibition of RAD51 foci formation and HR-mediated DNA double-strand break (DSB) repair.
    • Evaluated the efficacy and safety of lead compounds (CP-8 and CP-23) in vitro and in vivo, including combination studies with PARP inhibitors and gamma irradiation (γ-IR).

    Key Points:

    • Two novel nitroalkenes, (E)-8-nitro-nonadec-7-enoic acid (CP-8) and dimethyl (E)-nitro-oct-4-enedioate (CP-23), demonstrated superior TNBC cell killing and synergized with PARP inhibitors and γ-IR compared to CP-6.
    • CP-8 and CP-23 effectively inhibited γ-IR-induced RAD51 foci formation and HR, without affecting benign cells or cell cycle progression.
    • In vivo studies showed CP-8 exhibited promising anticancer activity alone and in combination with talazoparib in an HR-proficient TNBC mouse model, with preliminary toxicology suggesting safety.

    Conclusions:

    • CP-8 and CP-23 represent a novel class of nitroalkenes with potent anticancer activity against TNBC by targeting HR-mediated DNA repair.
    • CP-8 demonstrates significant therapeutic potential as a standalone agent or in combination therapy for HR-proficient TNBC.
    • Further development of CP-8 is warranted for treating cancers sensitive to homologous recombination-mediated DNA repair inhibitors.

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