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Enhancing PARP inhibitor efficacy using reduction-responsive nanoparticles encapsulating NADP.
J Mater Chem B
December 2024
Key Laboratory of Molecular Medicine and Biological Diagnosis and Treatment (Ministry of Industry and Information Technology), School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
Article Synopsis
- - Poly(ADP-ribose) polymerase inhibitors (PARPi), like olaparib, are effective in cancer treatment but not all tumors, including those with BRCA1/2 mutations, respond well to them.
- - NADP+ has been identified as a natural inhibitor that could enhance the effectiveness of PARPi, but its clinical use is limited due to its inability to effectively enter cells.
- - This study introduces nanoparticles that release NADP+ in tumor cells, increasing its concentration and working together with olaparib to significantly inhibit tumor growth, suggesting a new approach for cancer therapy.
Suppression of ADP-ribosylation reversal triggers cell vulnerability to alkylating agents.
Neoplasia
January 2025
Institute of Experimental Endocrinology and Oncology, National Research Council of Italy, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy. Electronic address:
The ADP-ribosyl hydrolases PARG and ARH3 counteract PARP enzymatic activity by removing ADP-ribosylation. PARG and ARH3 activities have a synthetic lethal effect; however, the specific molecular mechanisms underlying this response remain unknown. Here, we show that the PARG and ARH3 synthetic lethality is enhanced further in the presence of DNA alkylating agents, suggesting that the inability to revert ADP-ribosylation primarily affects the repair of alkylated DNA bases.
View Article and Find Full Text PDFMolecular mechanisms restoring olaparib efficacy through ATR/CHK1 pathway inhibition in olaparib-resistant BRCA1/2 ovarian cancer models.
Biochim Biophys Acta Mol Basis Dis
February 2025
Department of Medical Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska Street, 90-236 Lodz, Poland. Electronic address:
Article Synopsis
- Olaparib resistance in ovarian cancer patients calls for new strategies, leading to the creation of a patient-derived xenograft model to study this issue.
- In experiments, olaparib-resistant tumors were treated with olaparib alone, or combined with ATR and CHK1 inhibitors, revealing that these combinations effectively hindered tumor growth and altered key molecular signaling pathways.
- The study enhances our understanding of how to combat olaparib resistance in high-grade serous ovarian cancer with BRCA1/2 mutations, suggesting that targeting the ATR/CHK1 pathways could improve treatment outcomes for patients who are initially unresponsive to olaparib.
Is a Susceptibility Locus for Clarkson Disease (Monoclonal Gammopathy-Associated Systemic Capillary Leak Syndrome).
Arterioscler Thromb Vasc Biol
December 2024
Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases (E.C.C., A.J.A., A.D., K.M.D.), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD.
Article Synopsis
- Vascular leakage is a serious complication of severe infections like septicemia and malaria, leading to shock and multi-organ dysfunction, with a specific syndrome (MG-CLS) causing recurrent severe episodes triggered by minor infections.
- Researchers identified loss-of-function mutations in the PARP15 gene present in MG-CLS patients, linked to reduced enzyme function and increased vascular leakage.
- The PARP15 enzyme plays a crucial role in protecting blood vessel integrity during inflammation by inhibiting certain pathways, indicating a genetic factor influencing susceptibility to MG-CLS-related vascular issues.
Global remodeling of ADP-ribosylation by PARP1 suppresses influenza A virus infection.
bioRxiv
September 2024
Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI.
ADP-ribosylation is a highly dynamic and fully reversible post-translational modification performed by poly(ADP-ribose) polymerases (PARPs) that modulates protein function, abundance, localization and turnover. Here we show that influenza A virus infection causes a rapid and dramatic upregulation of global ADP-ribosylation that inhibits viral replication. Mass spectrometry defined for the first time the global ADP-ribosylome during infection, creating an infection-specific profile with almost 4,300 modification sites on ~1,080 host proteins, as well as over 100 modification sites on viral proteins.
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