Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Vermont, Burlington, VT, USA.
J Cachexia Sarcopenia Muscle. 2013 Jun;4(2):145-55. doi: 10.1007/s13539-012-0101-7. Epub 2013 Jan 24.
Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation. Inhibiting the signaling of the transcription factor nuclear factor kappa B (NF-κB) largely prevents cancer-induced muscle wasting in murine models. We have previously shown the utility of Compound A, a highly selective novel NF-κB inhibitor that targets the IκB kinase complex, to provide clinical benefit in cancer-induced skeletal muscle and cardiac atrophy.
Using a metabolomics approach, we describe the changes found between cachectic and noncachectic gastrocnemius muscles before and after Compound A treatment at various doses.
Of the 234 metabolites in the gastrocnemius, cachexia-induced changes in gastrocnemius metabolism reset the steady-state abundances of 42 metabolites (p < 0.05). These changes, not evenly distributed across biochemical categories, are concentrated in amino acids, peptides, carbohydrates and energetics intermediates, and lipids. The gastrocnemius glycolytic pathway is markedly altered-changes consistent with tumor Warburg physiology. This is the first account of a Warburg effect that is not exclusively restricted to cancer cells or rapidly proliferating nonmalignant cells. Cachectic gastrocnemius also displays tricarboxylic acid cycle disruptions, signs of oxidative stress, and impaired redox homeostasis. Compound A only partially rescues the phenotype of the cachectic gastrocnemius, failing to restore the gastrocnemius' baseline metabolic profile.
The findings in the present manuscript enumerate the metabolic consequences of cachexia in the gastrocnemius and demonstrate that NF-kB targeted treatment only partly rescues the cachectic metabolic phenotype. These data strengthen the previous findings from metabolomic characterization of serum in cachectic animals, suggesting that many of the metabolic alterations observed in the blood originate in the diseased muscle. These findings provide significant insight into the complex pathophysiology of cancer cachexia and provide objective criteria for evaluating future therapeutics.
癌症恶病质是一种严重的消耗性综合征，其特征是瘦肉组织逐渐减少和全身炎症。抑制转录因子核因子-κB（NF-κB）的信号传导在小鼠模型中能在很大程度上预防癌症引起的肌肉消耗。我们之前已经证明了新型 NF-κB 抑制剂化合物 A 的实用性，它可以靶向 IκB 激酶复合物，为癌症引起的骨骼肌和心脏萎缩提供临床益处。
我们使用代谢组学方法，描述了在不同剂量的化合物 A 治疗前后，恶病质和非恶病质腓肠肌之间发现的变化。
在腓肠肌中 234 种代谢物中，恶病质引起的腓肠肌代谢变化重置了 42 种代谢物的稳态丰度（p < 0.05）。这些变化在生化类别中分布不均，集中在氨基酸、肽、碳水化合物和能量中间产物以及脂质中。腓肠肌糖酵解途径发生明显改变——与肿瘤 Warburg 生理学一致的变化。这是首次报道不仅限于癌细胞或快速增殖的非恶性细胞的 Warburg 效应。恶病质腓肠肌还显示三羧酸循环中断、氧化应激迹象和氧化还原稳态受损。化合物 A 仅部分挽救恶病质腓肠肌的表型，未能恢复腓肠肌的基线代谢谱。
本研究阐述了恶病质在腓肠肌中的代谢后果，并表明 NF-κB 靶向治疗仅部分挽救恶病质的代谢表型。这些数据加强了以前在恶病质动物的代谢组学特征分析中发现的结果，表明在血液中观察到的许多代谢改变源自患病肌肉。这些发现为癌症恶病质的复杂病理生理学提供了重要的见解，并为评估未来治疗方法提供了客观的标准。
