Abstract
The natural phytoestrogen genistein is known as protein kinase inhibitor and tumor suppressor in various types of cancers. We studied its antitumor effect in two different xenograft models using positron emission tomography (PET) in vivo combined with ex vivo histology and nuclear magnetic resonance (NMR) metabolic fingerprinting.ProceduresA431 and Colo205 tumor-bearing mice were treated with vehicle or genistein (500 mg/kg/d) over a period of 12 days. Imaging was performed with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and 3′-deoxy-3′-[18F]fluorothymidine ([18F] FLT). In a second study A431 tumor-bearing mice were treated with vehicle, genistein (500 mg/kg/d), cetuximab (1mg/3d) or a combination of the compounds and imaged using [18F]FDG, [18F]FLT and [64Cu]NODAGA-cetuximab. Data were compared to histology and principal components analysis (PCA) of NMR fingerprinting data.ResultsGenistein reduced tumor growth significantly in both xenografts. [18F] FLT uptake was consistent in both models and corresponded to histological findings and also PCA whereas [18F]FDG and [64Cu]NODAGA-cetuximab were not suitable for therapy monitoring.ConclusionsAs mono-therapy the natural isoflavone genistein has a powerful therapeutic effect in vivo on A431 and Colo205 tumors. [18F]FLT has superior consistency compared to the other tested tracers in therapy monitoring, while the treatment effect could be shown on the molecular level by histology and metabolic fingerprinting.
Highlights
Phytoestrogens are natural compounds exhibiting a similar chemical structure to that of the sexual hormone 17β-estradiol
Genistein reduced tumor growth significantly in both xenografts. [18F] FLT uptake was consistent in both models and corresponded to histological findings and principal components analysis (PCA) whereas [18F]FDG and [64Cu]NODAGA-cetuximab were not suitable for therapy monitoring
As mono-therapy the natural isoflavone genistein has a powerful therapeutic effect in vivo on A431 and Colo205 tumors. [18F]FLT has superior consistency compared to the other tested tracers in therapy monitoring, while the treatment effect could be shown on the molecular level by histology and metabolic fingerprinting
Summary
Phytoestrogens are natural compounds exhibiting a similar chemical structure to that of the sexual hormone 17β-estradiol. The phytoestrogen genistein, 4′, 5, 7-trihydroxyisoflavone, is found in soybeans and soy products, and competes with 17β-estradiol for binding to the estrogen receptors ERα and ERβ inhibiting their activities and altering their mediated pathways [1]. Experiments demonstrated that genistein inhibits the activity of the epidermal growth factor receptor (EGFR), NFκB, ERK1/2 and Akt pathways, the insulin receptor, Abl and Src kinases [12, 13]. It potentiates the therapeutic effects of EGFR inhibitors such as gefitinib, erlotinib or cetuximab, which was shown in preclinical studies [2, 14, 15]
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