The emergence of chemoresistance poses a significant challenge to the efficacy of DNA-damaging agents in cancer treatment, in part due to the inherent DNA repair capabilities of cancer cells. The Ku70/80 protein complex (Ku) plays a central role in double-strand breaks (DSBs) repair through the classical non-homologous end joining (c-NHEJ) pathway, and has proven to be one of the most promising drug target for cancer treatment when combined with radiotherapy or chemotherapy. In this study, we conducted a high-throughput screening of small-molecule inhibitors targeting the Ku complex by using a fluorescence polarization-based DNA binding assay. From a library of 11,745 small molecules, UMI-77 was identified as a potent Ku inhibitor, with an IC₅₀ value of 2.3 μM. Surface plasmon resonance and molecular docking analyses revealed that UMI-77 directly bound the inner side of Ku ring, thereby disrupting Ku binding with DNA. In addition, UMI-77 also displayed potent inhibition against MUS81-EME1, a key player in homologous recombination (HR), demonstrating its potential for blocking both NHEJ- and HR-mediated DSB repair pathways. Further cell-based studies showed that UMI-77 could impair bleomycin-induced DNA damage repair, and significantly sensitized multiple cancer cell lines to the DNA-damaging agents. Finally, in a mouse xenograft tumor model, UMI-77 significantly enhanced the chemotherapeutic efficacy of etoposide with little adverse physiological effects. Our work offers a new avenue to combat chemoresistance in cancer treatment, and suggests that UMI-77 could be further developed as a promising candidate in cancer treatment.

01 Jun 2024·Aging Cell

Mitophagy defect mediates the aging‐associated hallmarks in Hutchinson–Gilford progeria syndrome

Article

Author: Sun, Yingying ; Zhang, Jin ; Xu, Le ; Wang, Gang ; Xia, Hongguang ; Fu, Xudong ; Wang, Jingjing ; Cao, Zhongkai ; Li, Yi ; Xu, Yuyan ; Cen, Xufeng ; Mao, Jianhua ; Liu, Zhihong ; Hu, Lidan ; Shen, Ning ; Jia, Shunze

AbstractHutchinson–Gilford progeria syndrome (HGPS) is a rare and fatal disease manifested by premature aging and aging‐related phenotypes, making it a disease model for aging. The cellular machinery mediating age‐associated phenotypes in HGPS remains largely unknown, resulting in limited therapeutic targets for HGPS. In this study, we showed that mitophagy defects impaired mitochondrial function and contributed to cellular markers associated with aging in mesenchymal stem cells derived from HGPS patients (HGPS‐MSCs). Mechanistically, we discovered that mitophagy affected the aging‐associated phenotypes of HGPS‐MSCs by inhibiting the STING‐NF‐ĸB pathway and the downstream transcription of senescence‐associated secretory phenotypes (SASPs). Furthermore, by utilizing UMI‐77, an effective mitophagy inducer, we showed that mitophagy induction alleviated aging‐associated phenotypes in HGPS and naturally aged mice. Collectively, our results uncovered that mitophagy defects mediated the aging‐associated markers in HGPS, highlighted the function of mitochondrial homeostasis in HGPS progression, and suggested mitophagy as an intervention target for HGPS and aging.

01 Jun 2024·CNS Neuroscience & Therapeutics

Hippocampal mitophagy contributes to spatial memory via maintaining neurogenesis during the development of mice

Article

Author: Xu, Le ; Zhang, Danhua ; Ma, Xinxu ; Xia, Hongguang ; Tian, Yanan ; Saeed, Saboor ; Sun, Yifei ; Tang, Anying ; Hu, Shaohua ; Zhou, Hetong ; Lai, Jianbo ; Zhang, Xuhong ; Cen, Xufeng

AbstractBackgroundImpaired mitochondrial dynamics have been identified as a significant contributing factor to reduced neurogenesis under pathological conditions. However, the relationship among mitochondrial dynamics, neurogenesis, and spatial memory during normal development remains unclear. This study aims to elucidate the role of mitophagy in spatial memory mediated by neurogenesis during development.MethodsAdolescent and adult male mice were used to assess spatial memory performance. Immunofluorescence staining was employed to evaluate levels of neurogenesis, and mitochondrial dynamics were assessed through western blotting and transmission electron microscopy. Pharmacological interventions further validated the causal relationship among mitophagy, neurogenesis, and behavioral performance during development.ResultsThe study revealed differences in spatial memory between adolescent and adult mice. Diminished neurogenesis, accompanied by reduced mitophagy, was observed in the hippocampus of adult mice compared to adolescent subjects. Pharmacological induction of mitophagy in adult mice with UMI‐77 resulted in enhanced neurogenesis and prolonged spatial memory retention. Conversely, inhibition of mitophagy with Mdivi‐1 in adolescent mice led to reduced hippocampal neurogenesis and impaired spatial memory.ConclusionThe observed decline in spatial memory in adult mice is associated with decreased mitophagy, which affects neurogenesis in the dentate gyrus. This underscores the therapeutic potential of enhancing mitophagy to counteract age‐ or disease‐related cognitive decline.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	The University of Michigan-Dearborn	-
Neoplasms	Preclinical	US	Barbara Ann Karmanos Cancer Institute	-

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