Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Nat Biotechnol. 2010 Mar;28(3):249-55. doi: 10.1038/nbt.1606. Epub 2010 Feb 14.
Most cells have the inherent capacity to shift their reliance on glycolysis relative to oxidative metabolism, and studies in model systems have shown that targeting such shifts may be useful in treating or preventing a variety of diseases ranging from cancer to ischemic injury. However, we currently have a limited number of mechanistically distinct classes of drugs that alter the relative activities of these two pathways. We screen for such compounds by scoring the ability of >3,500 small molecules to selectively impair growth and viability of human fibroblasts in media containing either galactose or glucose as the sole sugar source. We identify several clinically used drugs never linked to energy metabolism, including the antiemetic meclizine, which attenuates mitochondrial respiration through a mechanism distinct from that of canonical inhibitors. We further show that meclizine pretreatment confers cardioprotection and neuroprotection against ischemia-reperfusion injury in murine models. Nutrient-sensitized screening may provide a useful framework for understanding gene function and drug action within the context of energy metabolism.
大多数细胞都具有改变其糖酵解相对于氧化代谢的依赖程度的内在能力，模型系统的研究表明，针对这种转变可能有助于治疗或预防从癌症到缺血性损伤等各种疾病。然而，我们目前只有有限数量的具有不同作用机制的药物可以改变这两种途径的相对活性。我们通过评分超过 3500 种小分子在含有半乳糖或葡萄糖作为唯一糖源的培养基中选择性地损害人成纤维细胞生长和活力的能力来筛选这些化合物。我们确定了几种从未与能量代谢相关联的临床使用药物，包括止吐药美克洛嗪，它通过与经典抑制剂不同的机制来减弱线粒体呼吸。我们进一步表明，美克洛嗪预处理可在小鼠模型中提供针对缺血再灌注损伤的心脏和神经保护作用。营养敏感筛选可能为在能量代谢背景下理解基因功能和药物作用提供有用的框架。
