Inhibition of NAD+-Dependent Metabolic Processes Induces Cellular Necrosis and Tumor Regression in Rhabdomyosarcoma Models.

Autor:	McKay-Corkum GB; Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Collins VJ; Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Yeung C; Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Ito T; Urologic Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Issaq SH; Urologic Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Holland D; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health (NIH), Bethesda, Maryland., Vulikh K; Molecular Histopathology Lab, Frederick National Laboratory for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Zhang Y; National Clinical Target Validation Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Lee U; Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Lei H; Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Mendoza A; Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Shern JF; Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Yohe ME; Laboratory of Cell and Developmental Signaling, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Yamamoto K; Radiation Biology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Wilson K; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health (NIH), Bethesda, Maryland., Ji J; National Clinical Target Validation Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Karim BO; Molecular Histopathology Lab, Frederick National Laboratory for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Thomas CJ; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health (NIH), Bethesda, Maryland., Krishna MC; Radiation Biology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Neckers LM; Urologic Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland., Heske CM; Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Nov 01; Vol. 29 (21), pp. 4479-4491.
DOI:	10.1158/1078-0432.CCR-23-0200
Abstrakt:	Purpose: Deregulated metabolism in cancer cells represents a vulnerability that may be therapeutically exploited to benefit patients. One such target is nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage pathway. NAMPT is necessary for efficient NAD+ production and may be exploited in cells with increased metabolic demands. We have identified NAMPT as a dependency in rhabdomyosarcoma (RMS), a malignancy for which novel therapies are critically needed. Here we describe the effect of NAMPT inhibition on RMS proliferation and metabolism in vitro and in vivo. Experimental Design: Assays of proliferation and cell death were used to determine the effects of pharmacologic NAMPT inhibition in a panel of ten molecularly diverse RMS cell lines. Mechanism of the clinical NAMPTi OT-82 was determined using measures of NAD+ and downstream NAD+-dependent functions, including energy metabolism. We used orthotopic xenograft models to examine tolerability, efficacy, and drug mechanism in vivo. Results: Across all ten RMS cell lines, OT-82 depleted NAD+ and inhibited cell growth at concentrations ≤1 nmol/L. Significant impairment of glycolysis was a universal finding, with some cell lines also exhibiting diminished oxidative phosphorylation. Most cell lines experienced profound depletion of ATP with subsequent irreversible necrotic cell death. Importantly, loss of NAD and glycolytic activity were confirmed in orthotopic in vivo models, which exhibited complete tumor regressions with OT-82 treatment delivered on the clinical schedule. Conclusions: RMS is highly vulnerable to NAMPT inhibition. These findings underscore the need for further clinical study of this class of agents for this malignancy. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu