Artesunate (ART), a remarkable antimalarial agent, also inhibited the growth of human colorectal carcinoma. As determined by MTT assay, flow cytometry analysis on apoptosis and indirect immunofluorescence analysis on the proliferation-associated marker Ki67, ART suppressed the proliferation and promoted the apoptosis of colorectal cancer cells in a dose-dependent manner. Furthermore, immunofluorescence analysis on b-catenin and RT-PCR analysis on Wnt/b-catenin target genes demonstrated ART translocated b-catenin from nucleus to adherent junctions of membrane and reduced transcription mediated by b-catenin. These results suggested the anticancer activity of ART correlated with the inhibition of hyperactive Wnt/b-catenin signaling pathway. In vivo, ART significantly slowed the growth of colorectal tumor xenografts. Bioluminescent imaging also revealed that ART decreased the physiological activity of tumor xenografts and delayed spontaneous liver metastasis. These antitumor effects were related to the membranous translocation of b-catenin and the inhibition of the unrestricted activation of Wnt/b-catenin pathway, which was confirmed by the immunohistochemical staining of tumor tissues. These results and the known low toxicity are clues that ART might be a promising candidate drug for the treatment of colorectal carcinoma. ' 2007 Wiley-Liss, Inc.

BACKGROUND AND PURPOSE Mistletoe lectin‐I (ML‐I), the main anti‐cancer component of mistletoe extracts, was originally thought to act exclusively on 28S rRNA. Here, we investigate the down‐regulating effect and mechanism of CM‐1, an ML‐I isolated from Chinese mistletoe, on some miRNAs. EXPERIMENTAL APPROACH The anti‐cancer effects of CM‐1 were assessed in vitro and in vivo in colorectal cancer cells. The miRNAs down‐regulated by CM‐1 were identified by miRNA microarray assay and validated by qRT‐PCR analysis. The suppression of host gene transcription or by degradation of precursors was determined by qRT‐PCR and enzyme activity assays respectively. The qRT‐PCR, Western blot and immunohistochemistry were used to examine the expression of their target gene and related downstream effector. Cell proliferation was assayed in stably transfected HEK‐293 cells with different levels of these miRNAs. KEY RESULTS CM‐1 showed prominent anti‐neoplastic activity towards CLY and HT‐29 cells both in vitro and in vivo. The miR‐135a&b were the miRNAs most down‐regulated by CM‐1. Their host gene transcription was largely up‐regulated, while their precursors were degraded directly by CM‐1. The expression of their target gene adenomatous polyposis coli and the phosphorylation of related effector β‐catenin were both significantly up‐regulated. The IC50 values of CM‐1 on derivative HEK‐293 cells with high miR‐135a&b levels were 2–4 times lower than that of control cells. CONCLUSIONS AND IMPLICATIONS CM‐1 down‐regulated some miRNAs by degrading their precursors, which contributes to its prominent anti‐cancer activity. LINKED ARTICLE This article is commented on by Rushworth, pp. 346–348 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.01075.x

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The critical role of VEGFR2 in tumor neovascularization and progression has allowed the design of clinically beneficial therapies based on it. Here we show that BC001, a new fully human anti-VEGFR2 monoclonal antibody, inhibits VEGF-stimulated endothelial cell migration, tube formation, and effectively suppressed the transdifferentiation of cancer stem cells into endothelial cells in vitro. Since BC001 exhibited no activity against the mouse VEGFR2 and mouse based study was required to confirm its efficacy in vivo, BC101, the mouse analogue of BC001, was developed. BC101 significantly attenuated angiogenesis according to Matrigel plug assay and resulted in ~80% growth inhibition of mouse B16F10 homograft tumors relative to vehicle control. Similarly, human analogue BC001 suppressed the growth of human xenograft tumors HCT116 and BGC823. Furthermore, immunohistochemical results showed reduced expression of CD31, VEGFR2 and Ki-67, as well as increased expression of Caspase 3 in BC001-treated tumor, which indicated BC001 was able to significantly decrease microvessel density, suppress proliferation and promote apoptosis. These results demonstrate the fully human VEGFR2 monoclonal antibody BC001 can work as an effective inhibitor of tumor angiogenesis and tumor growth both in vitro and in vivo.

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