2020年7月26日
Sirtuin activation targets IDH-mutant tumors.
Neuro-oncology
- 巻
- 23
- 号
- 1
- 開始ページ
- 53
- 終了ページ
- 62
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1093/neuonc/noaa180
BACKGROUND: 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 small molecules, CRISPR/Cas9 gene editing and 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 nicotinamide phosphoribosyltransferase inhibition (NAMPTi), 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 non-toxic STACs, administered either alone or in combination with NAMPTi, could alter the growth trajectory of IDH-mutant gliomas, while minimizing toxicity associated with cytotoxic chemotherapeutic regimens.
- リンク情報
- ID情報
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- DOI : 10.1093/neuonc/noaa180
- PubMed ID : 32710757
- PubMed Central 記事ID : PMC7850026