Abstract
BackgroundThe invasion of colon cancer is associated with the tumor angiogenesis. Endostatin is an important anti-angiogenic agent, and the additive effect of endostatin with a chemotherapeutic agent, cyclophosphamide, on micrangium has not been established.MethodsMale BALB/c strain nude mice were injected with human colorectal carcinoma cells (HCT-116). The mice were divided into four groups (n = 15, each group) and were treated with different concentrations of endostatin (15, 10, and 5 mg/kg/day), cyclophosphamide (20, 10, and 5 mg/kg/day), and combination of endostatin/cyclophosphamide (15 + 20, 15 + 10, and 15 + 5 mg/kg/day). The tumor inhibition rate was evaluated, followed by the quantification of messenger ribonucleic acid (mRNA) and protein expression of notch signaling components NOTCH-1, NOTCH-3, NOTCH-4, JAG-1, DLL-4, Hes-1, and Hey-1 using quantitative polymerase chain reaction (qPCR). The protein expression of NOTCH-3, JAG-1, and DLL-4 was confirmed using western blotting. Microvessel density (MVD) was evaluated to detect micrangium following the treatment.ResultsThe endostatin/cyclophosphamide-treated samples exhibited an additive effect on the tumor inhibition rate and the microvessel count. NOTCH-1, NOTCH-3, NOTCH-4, JAG-1, Hes-1, and Hey-1 expression levels were highly correlated and downregulated in the treated samples, whereas DLL-4 expression was upregulated that accounted for its anti-angiogenic property.ConclusionsThe combination treatment of colon cancer with endostatin and a chemotherapeutic agent, cyclophosphamide proves to be an efficient therapeutic strategy to inhibit the rapid vasculature formation confirmed by the differential expression of notch signaling components.
Highlights
The invasion of colon cancer is associated with the tumor angiogenesis
Notch receptors are cleaved with the activated γ-secretase to release the active notch intracellular domain (NICD) which is translocated from the nucleus to bind to the transcriptional factors and recruits co-activators
We examined the expression of notch signaling receptor NOTCH-1, NOTCH-3, NOTCH-4, ligands JAG1 and DLL-4 along with the downstream targets Hes-1 and Hey-1 to determine the efficacy of a combined therapeutic strategy with endostatin/cyclophosphamide (CTX) to normalize the tumor micrangium associated with colon cancer
Summary
The invasion of colon cancer is associated with the tumor angiogenesis. Endostatin is an important anti-angiogenic agent, and the additive effect of endostatin with a chemotherapeutic agent, cyclophosphamide, on micrangium has not been established. Angiogenesis forms an important factor in the rapid expansion of tumors by promoting the process of metastasis [2, 3]. The notch signaling pathway plays a pivotal role in the tumor angiogenesis by promoting progenitor/stem cell proliferation [15]. Notch receptors are cleaved with the activated γ-secretase to release the active notch intracellular domain (NICD) which is translocated from the nucleus to bind to the transcriptional factors and recruits co-activators. These co-activators induce the notch downstream target gene expression (Hes-1) that activates the notch signaling pathway [18]. The notch signaling pathway is aberrantly activated during colon carcinogenesis and has been reported to be essential in maintaining the development of the intestinal cells [19]
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