Local inhibition of angiogenesis by halofuginone coated silicone materials

Abstract

Anti-angiogenic therapy is a promising approach for the treatment of increased angiogenesis in certain diseases. We aimed to investigate the local anti-angiogenic effect of silicone implants coated with Halofuginone, an angiogenesis inhibitor that inhibits synthesis of collagen-type-I and matrix metalloproteinases. The degree of angiogenesis was observed after implantation of surface modified Halofuginone eluting silicone implants into a submuscular pocket in rats over a period of 3 months. Subsequently, key mediators of angiogenesis (TGF-beta-1, bFGF, COL1A1, MMP-2, MMP-9, VEGF and PDGF) were established by immunohistological staining and RT-PCR and statistically evaluated. In comparison to uncoated silicone implants, Halofuginone eluting silicone implants lead to a significant local decrease of angiogenesis. Halofuginone eluting hybrid surface silicone implants have a significant local anti-angiogenic effect by down-regulating the expression activity of key mediators of angiogenesis.

Halofuginone inhibits phosphorylation of SMAD-2 reducing angiogenesis and leukemia burden in an acute promyelocytic leukemia mouse model

“…In the leukemia mouse model, we did observe increased gene expression of VEGF, HIF-1α and ANGPT-2, which were significantly reduced after HF treatment. These PCR data support that HF antiangiogenic effect implicates multiple targets, as demonstrated by Jordan ans Zeplin [ 25 ], MMP-2, bFGF and TGF-β were down-modulated by HF in physiologic conditions.…”

“…Jordan and Zeplin, showed that HF significantly reduces the gene expression of pro-angiogenic factors in physiologic conditions in muscle cells [ 25 ]. In order to evaluate the effect of HF in leukemic cells, we treated the APL cell line NB4 and performed a screening of gene expression using the PCR array method analyzing 84 predefined genes involved in angiogenesis (Additional file 2 : Table S2).…”

“…Elkin et al [ 24 ] reported that HF treatment led to the reduction in metalloproteinase-2 (MMP-2) expression and inhibition of bladder carcinoma metastasis in an animal model. However, HF effects may not be specific to malignant tissues, since the implant of silicone coated with HF resulted in reduced expression of MMP-2, bFGF and TGF-β in normal muscle [ 25 ]. In APL the TGF-β pathway is deregulated by the cytoplasmic PML isoform (cPML) [ 26 ] and we have demonstrated that HF inhibited cell proliferation and induced apoptosis in the APL cell line NB4 through modulation of TGF-β-target genes, such as c-Myc and p21 [ 1 ].…”

Inhibition of matrix metalloproteinase-2 by halofuginone is mediated by the Egr1 transcription factor

“…Upregulation of Egr1 and Egr-2 was observed at 1-5 and 3 h, respectively, followed by a marked decrease thereafter. 4) and in a recent study evaluating the antiangiogenic effect of halofuginone [46]. Expression of MMP-2 and TIMP-2 was downregulated after 8 h of halufuginone treatment, whereas that of heparanase (HPSE) and TIMP-1 was unaffected.…”

Halofuginone may suppresses azoxymethane-induced serum tumor necrosis factor-a synthesis and aberrant crypt foci progression in rat colon

“…It has been reported that HLF may induce apoptosis and reduce cancer volume in experimentally induced colon cancer in the nude mouse (Chen et al, 2015). It may also have antiangiogenic, antimetastatic and antiproliferative effects, increase apoptosis/necrosis, and decrease collagen content in other cancer types (Gavish et al, 2002;Grudzien et al, 2010;Jordan and Zeplin, 2012). Further, HLF may enhance the effects of chemotherapeutic agents on cancer (Leiba et al, 2012).…”