Radiosensitizing efficacy of diosmin-hesperidin complex against ehrlich solid carcinoma in mice, a potential role of histone deacetylase and pro-angiogenic chaperones targeting

Abstract

Background and Objective: Adaptation to hypoxic microenvironment is critical for tumor survival and metastatic spread. Hypoxia inducible factor-1α (HIF-1α) plays a key role in this adaptation by stimulating the production of proangiogenic factors and inducing enzymes necessary for anaerobic metabolism. Histone deacetylase inhibitors (HDACIs) produce a marked inhibition of HIF-1α expression and are currently in clinical trials partly based on their potent antiangiogenic effects. Thus, the current study was conducted to evaluate the possible effect of diosmin-hesperidin complex (daflon®) as a radiosensitizing and anti-angiogenic natural product against Ehrlich solid carcinoma (ESC) in mice as a model for solid tumor. Materials and Methods: Mice were treated with diosmin-hesperidin complex (daflon® D; 100 mg kgG1 B.Wt., orally for 4 weeks after ESC induction) and exposed to a total body (-radiation (R; 2 Gy/week for 4 weeks up to a total dose of 8 Gy). Cytotoxicity of D was assessed by MTT assay and animal 30 days survival after tumor induction was determined. Histone deacetylase (HDAC) activity, HIF-1α, heat shock protein-90 and -70 (HSP-90 and 70), vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS) and survivin levels were determined in tumor tissue. Statistical analysis was performed using one way analysis of variance (ANOVA) followed by Holm-Sidak as a post-hoc test estimated by Sigma Plot 11. Results: The obtained results showed a significant increase (p<0.05) in tumor tissue levels of VEGF, HIF-1α, HSP-90 and -70 and survivin as well as HDAC and iNOS activities in E group. Combination of D with R in ESC bearing mice resulted in a remarkable decrease in the aforementioned biochemical parameters in tumor tissue, which was indicated by significant tumor volume regression and mice survival. Conclusion: This study confirms the anti-angiogenic and radiosensitizing effect of D mediated via inhibiting HDAC activity and disruption of HIF-1α-HSP-70/90 signaling axis in ESC xenograft model.