{"doi":"10.1093/neuonc/noaa180","title":"Sirtuin activation targets IDH-mutant tumors","abstract":"BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant tumors exhibit an altered metabolic state and are critically dependent upon nicotinamide adenine dinucleotide (NAD+) for cellular survival. NAD+ steady-state levels can be influenced by both biosynthetic and consumptive processes. Here, we investigated activation of sirtuin (SIRT) enzymes, which consume NAD+ as a coenzyme, as a potential mechanism to reduce cellular NAD+ levels in these tumors. METHODS: The effect of inhibition or activation of sirtuin activity, using (i) small molecules, (ii) clustered regularly interspaced short palindromic repeat/CRISPR associated protein 9 gene editing, and (iii) inducible overexpression, was investigated in IDH-mutant tumor lines, including patient-derived IDH-mutant glioma lines. RESULTS: We found that Sirt1 activation led to marked augmentation of NAD+ depletion and accentuation of cytotoxicity when combined with inhibition of nicotinamide phosphoribosyltransferase (NAMPT), consistent with the enzymatic activity of SIRT1 as a primary cellular NAD+ consumer in IDH-mutant cells. Activation of Sirt1 through either genetic overexpression or pharmacologic Sirt1-activating compounds (STACs), an existing class of well-tolerated drugs, led to inhibition of IDH1-mutant tumor cell growth. CONCLUSIONS: Activation of Sirt1 can selectively target IDH-mutant tumors. These findings indicate that relatively nontoxic STACs, administered either alone or in combination with NAMPT inhibition, could alter the growth trajectory of IDH-mutant gliomas while minimizing toxicity associated with cytotoxic chemotherapeutic regimens.","journal":"Neuro-Oncology","year":2020,"id":98605,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":31,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9698,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":487514,"name":"Alexandria L. Fink","orcid":null,"position":1,"is_corresponding":false},{"id":487515,"name":"Jack A Banagis","orcid":null,"position":2,"is_corresponding":false},{"id":271741,"name":"Hiroaki Nagashima","orcid":"0000-0003-0685-7382","position":3,"is_corresponding":false},{"id":281421,"name":"Megha Subramanian","orcid":"0000-0002-4416-5128","position":4,"is_corresponding":false},{"id":68072,"name":"Christine K. Lee","orcid":"0000-0003-1422-4606","position":5,"is_corresponding":false},{"id":281422,"name":"Lisa Melamed","orcid":"0009-0008-5204-5135","position":6,"is_corresponding":false},{"id":486392,"name":"Shilpa S. Tummala","orcid":"0000-0003-3371-2859","position":7,"is_corresponding":false},{"id":281420,"name":"Kensuke Tateishi","orcid":"0000-0001-6895-9013","position":8,"is_corresponding":false},{"id":25157,"name":"Hiroaki Wakimoto","orcid":"0000-0001-8225-241X","position":9,"is_corresponding":false},{"id":11409,"name":"Daniel P. Cahill","orcid":"0000-0003-2552-6546","position":10,"is_corresponding":false},{"id":281423,"name":"Julie J. Miller","orcid":"0000-0002-1288-593X","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-18T22:36:58.511143Z","pmid":"32710757","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}