小柯机器人

美国冷泉港实验室Tobias Janowitz团队近期取得重要工作进展，他们研究发现生酮饮食促进肿瘤铁死亡，但诱导相对皮质酮缺乏并加速恶病质。相关研究成果2023年6月12日在线发表于《细胞—代谢》杂志上。

据介绍，癌症细胞的葡萄糖依赖性可以通过高脂肪、低碳水化合物的生酮饮食（KD）进行治疗。然而，在产生IL-6的癌症中，肝生酮潜能的抑制阻碍了KD作为生物体能量的利用。

在IL-6相关的癌症恶病质小鼠模型中，研究人员描述了喂食KD的小鼠肿瘤生长延迟，但恶病质发作加快，生存期缩短。从机制上讲，这种解偶联是两种NADPH依赖性途径的生物化学相互作用的结果。在肿瘤内，脂质过氧化的增加以及谷胱甘肽（GSH）系统的饱和导致癌症细胞的铁中毒死亡。系统地说，氧化还原失衡和NADPH耗竭损害皮质酮的生物合成。地塞米松是一种强效的糖皮质激素，它可以增加食物摄入量，使葡萄糖水平和营养底物的利用正常化，延缓恶病质的发作，并延长喂食KD的荷瘤小鼠的生存期，同时保持肿瘤生长的减少。

总之，这一研究强调，需要研究系统干预对肿瘤和宿主的影响，以准确评估治疗潜力。这些发现可能与研究癌症患者营养干预（如KD）的临床研究工作有关。

附：英文原文

Title: Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia

Author: Miriam Ferrer, Nicholas Mourikis, Emma E. Davidson, Sam O. Kleeman, Marta Zaccaria, Jill Habel, Rachel Rubino, Qing Gao, Thomas R. Flint, Lisa Young, Claire M. Connell, Michael J. Lukey, Marcus D. Goncalves, Eileen P. White, Ashok R. Venkitaraman, Tobias Janowitz

Issue&Volume: 2023-06-12

Abstract: Glucose dependency of cancer cells can be targeted with a high-fat, low-carbohydrateketogenic diet (KD). However, in IL-6-producing cancers, suppression of the hepaticketogenic potential hinders the utilization of KD as energy for the organism. In IL-6-associatedmurine models of cancer cachexia, we describe delayed tumor growth but acceleratedcachexia onset and shortened survival in mice fed KD. Mechanistically, this uncouplingis a consequence of the biochemical interaction of two NADPH-dependent pathways. Withinthe tumor, increased lipid peroxidation and, consequently, saturation of the glutathione(GSH) system lead to the ferroptotic death of cancer cells. Systemically, redox imbalanceand NADPH depletion impair corticosterone biosynthesis. Administration of dexamethasone,a potent glucocorticoid, increases food intake, normalizes glucose levels and utilizationof nutritional substrates, delays cachexia onset, and extends the survival of tumor-bearingmice fed KD while preserving reduced tumor growth. Our study emphasizes the need toinvestigate the effects of systemic interventions on both the tumor and the host toaccurately assess therapeutic potential. These findings may be relevant to clinicalresearch efforts that investigate nutritional interventions such as KD in patientswith cancer.

DOI: 10.1016/j.cmet.2023.05.008

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00185-7

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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