Metabolic Transformation of DMBA-Induced Carcinogenesis and Inhibitory Effect of Salvianolic Acid B and Breviscapine Treatment

Abstract

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.

Metabolic transformation of breast cancer in a MCF-7 xenograft mouse model and inhibitory effect of volatile oil from Saussurea lappa Decne treatment

“…2.6 Serum sample preparation and analysis by GC-TOF/MS Serum samples were derivatized and subsequently analyzed by GC-TOF/MS, based on the report of Wei et al (2012) with minor modifications. A 50 lL aliquot of serum sample was spiked with 10 lL mixed internal standards (0.3 mg/mL 2-chlorophenylalanine and 1 mg/mL heptadecanoic acid in methanol) and vortexed for 10 s. The mixed solution was extracted with 150 lL of methanolacetonitrile (2:1, v/v) and vortexed for 30 s. After storing for 10 min at -20°C, the samples were centrifuged at 15,0009g for 10 min at 4°C.…”

Metabolomics for tumor marker discovery and identification based on chromatography–mass spectrometry

“…The carcinogenesis-induced metabolic deregulation of glutaminolysis, glycolysis, cholesterol and myoinositol metabolisms was ameliorated by the agents. The results implied that the changes of metabolic profiles could be sensitive indicators of antineoplastic effects [98]. Thus, it is feasible to identify biomarkers for the personalized treatment of malignancies.…”

“…Sarcosine was reported to classify low-and high-grade PCa [78]. Wei and colleagues evaluated the inhibitory effects of two antineoplastic agents (salvianolic acid B and breviscapine) on oral carcinogenesis using a GC-TOF platform [98]. The carcinogenesis-induced metabolic deregulation of glutaminolysis, glycolysis, cholesterol and myoinositol metabolisms was ameliorated by the agents.…”

Salvianolic acid B suppresses cell proliferation and induces apoptosis in osteosarcoma through p38-mediated reactive oxygen species generation

“…Clinically, injections of Danshen may expand blood vessels, increase coronary artery blood flow and promote the recovery of ischemic or damaged myocardium, and may treat multiple types of cardiovascular disease (13). In terms of antineoplastic research, the water-soluble components of Danshen may inhibit the growth of multiple types of tumor, promote tumor cell apoptosis and inhibit tumor angiogenesis (14). Salvianolic acid B, as illustrated in Fig.…”

“…Salvianolic acid B possess anti-oxidative and anti-inflammation effects (16). At present, salvianolic acid B has been demonstrated to exhibit the strongest pharmacological activity in Danshen water-soluble substances (14). Recently, salvianolic acid B was the focus of a study investigating myocardial regeneration, angiogenesis, reversion ventricular remodeling and ischemic peripheral vascular disease (17).…”