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Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) with OT-82 induces DNA damage, cell death, and suppression of tumor growth in preclinical models of Ewing sarcoma.

التفاصيل البيبلوغرافية
العنوان: Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) with OT-82 induces DNA damage, cell death, and suppression of tumor growth in preclinical models of Ewing sarcoma.
المؤلفون: Gibson AE; Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Yeung C; Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Issaq SH; Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.; Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Collins VJ; Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Gouzoulis M; Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Zhang Y; National Clinical Target Validation Laboratory, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Ji J; National Clinical Target Validation Laboratory, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Mendoza A; Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Heske CM; Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Christine.heske@nih.gov.
المصدر: Oncogenesis [Oncogenesis] 2020 Sep 10; Vol. 9 (9), pp. 80. Date of Electronic Publication: 2020 Sep 10.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101580004 Publication Model: Electronic Cited Medium: Print ISSN: 2157-9024 (Print) Linking ISSN: 21579024 NLM ISO Abbreviation: Oncogenesis Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: New York, NY : Nature Pub. Group
مستخلص: NAMPT mediates the rate-limiting step of the NAD salvage pathway, which maintains cellular bioenergetics and provides a necessary substrate for functions essential to rapidly proliferating cancer cells. In this study, we evaluated the efficacy and mechanisms of action of OT-82, a novel, high-potency NAMPT inhibitor with a favorable toxicity profile, in preclinical models of Ewing sarcoma (EWS), an aggressive pediatric malignancy with previously reported selective sensitivity to NAMPT inhibition. We show that OT-82 decreased NAD concentration and impaired proliferation of EWS cells in a dose-dependent manner, with IC 50 values in the single-digit nanomolar range. Notably, genetic depletion of NAMPT phenocopied pharmacological inhibition. On-target activity of OT-82 was confirmed with the addition of NMN, the product of NAMPT, which rescued NAD concentration and EWS cellular viability. Mechanistically, OT-82 treatment resulted in impaired DNA damage repair through loss of PARP activity, G2 cell-cycle arrest, and apoptosis in EWS cells. Additional consequences of OT-82 treatment included reduction of glycolytic and mitochondrial activity. In vivo, OT-82 impaired tumor growth and prolonged survival in mice bearing EWS xenografts. Importantly, antitumor effect correlated with pharmacodynamic markers of target engagement. Furthermore, combining low-dose OT-82 with low doses of agents augmenting DNA damage demonstrated enhanced antitumor activity in vitro and in vivo. Thus, OT-82 treatment represents a potential novel targeted approach for the clinical treatment of EWS.
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تواريخ الأحداث: Date Created: 20200910 Latest Revision: 20210910
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC7481307
DOI: 10.1038/s41389-020-00264-0
PMID: 32908120
قاعدة البيانات: MEDLINE
الوصف
تدمد:2157-9024
DOI:10.1038/s41389-020-00264-0