Department of Oral Mucosal Diseases, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai Key Laboratory of Stomatology, Shanghai 200011, China.
J Proteome Res. 2012 Feb 3;11(2):1302-16. doi: 10.1021/pr2009725. Epub 2011 Dec 19.
Oral cancer typically develops from hyperplasia through dysplasia to carcinoma with a multistep process of carcinogenesis involving genetic alterations resulting in aberrant cellular appearance, deregulated cell growth, and carcinoma. The metabolic transformation during the process of oral carcinogenesis and its implications for cancer therapy have not been extensively investigated. Here, we report a metabonomic study on a classical model of 7,12-dimethylbenz(a)anthracene (DMBA)-induced oral carcinogenesis in hamsters to delineate characteristic metabolic transformation during the carcinogenesis using gas chromatography time-of-flight mass spectrometry (GC-TOF MS). Salvianolic acid B (Sal-B), isolated from Salvia miltiorrhiza Bge, and Breviscapine, a flavonoid isolated from Herba Erigerontis, were used to treat the hamsters exposed to DMBA to investigate the molecular mechanism of the inhibitory effect of the two agents on oral carcinogenesis. The dynamic changes of serum metabolic profiles indicated that both Sal-B and Breviscapine were able to attenuate DMBA-induced metabolic perturbation, which is consistent with the histopathological findings that Sal-B and Breviscapine significantly decreased the squamous cell carcinoma (SCC) incidence in the two treatment groups. Significant alterations of key metabolic pathways, including elevated glutaminolysis and glycolysis, and decreased cholesterol and myo-inositol metabolism, were observed in the DMBA-induced model group, which were attenuated or normalized by Sal-B or Breviscapine treatment. Elevated inflammation and tumor angiogenesis at gene and metabolite expression levels were also observed in DMBA-induced oral dysplasia and SCC but were attenuated or normalized by Sal-B and Breviscapine along with significantly decreased incidences of SCC formation.
口腔癌通常通过增生、异型增生发展为癌，其发生是一个多步骤的过程，涉及遗传改变导致细胞异常、细胞生长失控和癌变。在口腔癌变过程中的代谢转化及其对癌症治疗的影响尚未得到广泛研究。在这里，我们报告了一个经典的 7,12-二甲基苯并（a）蒽（DMBA）诱导的仓鼠口腔癌变模型的代谢组学研究，使用气相色谱飞行时间质谱（GC-TOF MS）描绘癌变过程中的特征代谢转化。丹酚酸 B（Sal-B）从丹参中分离得到，灯盏花乙素是从灯盏细辛中分离得到的一种黄酮类化合物，用于治疗暴露于 DMBA 的仓鼠，以研究两种药物抑制口腔癌变的分子机制。血清代谢谱的动态变化表明，Sal-B 和灯盏花乙素均能减弱 DMBA 诱导的代谢紊乱，这与组织病理学发现一致，即 Sal-B 和灯盏花乙素显著降低了两组治疗组的鳞状细胞癌（SCC）发生率。在 DMBA 诱导的模型组中观察到关键代谢途径的显著改变，包括谷氨酰胺分解和糖酵解升高，胆固醇和肌醇代谢降低，而 Sal-B 或灯盏花乙素治疗可减弱或使这些改变正常化。在 DMBA 诱导的口腔异型增生和 SCC 中，还观察到基因和代谢物表达水平的炎症和肿瘤血管生成升高，但 Sal-B 和灯盏花乙素可减弱或使这些改变正常化，同时 SCC 形成的发生率显著降低。
