Small-molecule inhibitors of DNA repair pathways are being intensively investigated as primary and adjuvant chemotherapies. We report the discovery that cardiac glycosides, natural products in clinical use for the treatment of heart failure and atrial arrhythmia, are potent inhibitors of DNA double-strand break (DSB) repair. Our data suggest that cardiac glycosides interact with phosphorylated mediator of DNA damage checkpoint protein 1 (phospho-MDC1) or E3 ubiquitin-protein ligase ring finger protein 8 (RNF8), two factors involved in DSB repair, and inhibit the retention of p53 binding protein 1 (53BP1) at the site of DSBs. These observations provide an explanation for the anticancer activity of this class of compounds, which has remained poorly understood for decades, and provide guidance for their clinical applications. This discovery was enabled by the development of the first high-throughput unbiased cellular assay to identify new small-molecule inhibitors of DSB repair. Our assay is based on the fully automated, time-resolved quantification of phospho-SER139-H2AX (γH2AX) and 53BP1 foci, two factors involved in the DNA damage response network, in cells treated with small molecules and ionizing radiation (IR). This primary assay is supplemented by robust secondary assays that establish lead compound potencies and provide further insights into their mechanisms of action. Although the cardiac glycosides were identified in an evaluation of 2366 small molecules, the assay is envisioned to be adaptable to larger compound libraries. The assay is shown to be compatible with small-molecule DNA cleaving agents, such as bleomycin, neocarzinostatin chromophore, and lomaiviticin A, in place of IR.
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http://dx.doi.org/10.1021/jacs.6b00162 | DOI Listing |
Oncol Rep
February 2025
Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan.
BH3 mimetics are small‑molecule inhibitors of the antiapoptotic Bcl‑2 family and have therapeutic efficacy against hematological malignancies. BH3 mimetic A‑1331852 suppresses colorectal cancer cell proliferation. Progressive resistance to the widely used anticancer agent fluorouracil (5‑FU) is a key reason for colorectal cancer recurrence; therefore, the present study tested if A‑1331852 can suppress the proliferation of 5‑FU‑resistant colorectal cancer cells.
View Article and Find Full Text PDFVirus Evol
November 2024
Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Herestraat 49 box 1043, Leuven 3000, Belgium.
The widespread use of antivirals in immunocompromised individuals has led to frequent occurrences of drug-resistant herpes simplex virus 1 (HSV-1) infections. Current antivirals target the viral DNA polymerase (DP), resulting in cross-resistance patterns that emphasize the need for novel treatment strategies. In this study, we assessed whether combining antivirals with different targets affects drug resistance emergence by passaging wild-type HSV-1 under increasing concentrations of acyclovir (ACV), foscarnet (phosphonoformic acid, PFA), or the helicase-primase inhibitor pritelivir (PTV), individually or in combination (ACV + PTV or PFA + PTV).
View Article and Find Full Text PDFAm J Physiol Cell Physiol
December 2024
Department of Synthesis and Technology of Drugs, Medical University of Białystok, Kilińskiego 1, 15-089 Białystok, Poland.
Many pathogens including viruses enter cells by endocytosis. We identified and evaluated novel endocytosis inhibitors capable of blocking the entry of the HIV-1 Tat protein into neuronal cells and investigated their potential protective properties against Tat-induced neurotoxicity. In this study, the compounds Les-6631 and Les-6633 were synthesized and assessed.
View Article and Find Full Text PDFArch Toxicol
December 2024
Faculty of Medicine, Rudolf Schönheimer Institute of Biochemistry, Leipzig University, Leipzig, Germany.
The Hedgehog (Hh) signaling pathway is essential for maintaining homeostasis during embryogenesis and in adult tissues. In the liver, dysregulation of this pathway often leads to liver cancer development. Recent studies also suggest that disturbances in the Hh pathway can affect liver metabolism in healthy livers through interactions with other signaling pathways, such as the Wnt/β-catenin pathway.
View Article and Find Full Text PDFMuscle Nerve
December 2024
Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.
Introduction And Aims: Mitochondrial myopathies are rare genetic disorders for which no effective treatment exists. We previously showed that the pharmacological cyclophilin inhibitor cyclosporine A (CsA) extends the lifespan of fast-twitch skeletal muscle-specific mitochondrial transcription factor A knockout (Tfam KO) mice, lacking the ability to transcribe mitochondrial DNA and displaying lethal mitochondrial myopathy. Our present aim was to assess whether the positive effect of CsA was associated with improved in vivo mitochondrial energy production.
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