Research from Aeyung Kim and Minju Im shows that Suppression of MMP-9 activity and VEGF production resulting in reduction of metastatic and angiogenic potency of malignant cancer by Eupatorium fortunei.

In this study, they used CM from tumor cells as an inducer to stimulate endothelial cells for an in vitro angiogenesis assay to mimic in vivo tumor-induced angiogenesis. As reported by Ito et al, they observed that CM from HT1080 cells promoted the growth of HUVECs and increased tube formation on Matrigel. In contrast, WEF-treated tumor cells showed decreased production of MMP-9 in the CM; consequently, proteolytic activity against gelatin and collagen, and migration/invasion through Matrigel by WEF-treated cells were lower than those by control cells. WEF also inhibited the production of VEGF-α by tumor cells, thereby suppressing tumor-induced capillary-like tube formation and HUVEC migration. Furthermore, WEF-treated CM suppressed sprouting in an ex vivoaortic ring assay. In a Matrigel plug assay, the WEF-containing tumor xenograft showed not only a significant reduction in growth, but also decreased neovascularization, supporting the in vivo anti-angiogenic potency of WEF. WEF had no direct effect on endothelial cells in terms of migration, tube formation, or angiogenesis. Collectively, these results suggest that WEF has anti-metastatic and anti-angiogenic potency, targeting cancer cells but not endothelial cells.

In response to PMA stimulation, MAPK activation and subsequent NF-κB activation occurred, resulting in MMP-9 activation, which is involved in cancer cell adhesion, invasion, and angiogenesis. In this study, they found that WEF almost completely blocked PMA-induced p38 and JNK phosphorylation, and dramatically decreased PMA-induced NF-κB activation, consequently suppressing cellular metastatic potential by down regulating MMP-9 activity. PC-3 and HT1080 cells also produced high levels of VEGF under normoxic conditions, and WEF inhibited VEGF expression. Under hypoxic conditions, PC-3 and HT1080 cells accumulated HIF-1α, which activates VEGF expression by binding the hypoxia response element in the VEGF promoter region, and which plays a pivotal role in tumor adaptation to the microenvironment. It has been reported that HIF-1α is overexpressed in many human cancers and their metastatic foci, and it correlates with increased vessel density and resistance to chemo/radiotherapy. Thus, factors that regulate HIF-1α activity are potential targets for cancer treatment. As shown in Figures 1, WEF inhibited hypoxia-induced HIF-1α accumulation by suppressing Akt/mTOR signaling, supporting the finding that WEF inhibited PC-3 tumor xenograft growth and angiogenesis in nude mice (Figures 1).

In summary, their data indicate that WEF exerted anti-metastatic and anti-angiogenic effects on malignant cancer cells both in vitro and in vivo by targeting key molecules involved in tumor progression, including MMP-9 and VEGF. Furthermore, they observed the potent therapeutic efficacy of WEF against pulmonary metastasis in mice, with no apparent side effects. These results indicate that WEF may be a candidate agent against malignant metastatic human cancers.

Reference

Aeyung Kim, Minju Im, Nam-Hui Yim and Jin Yeul Ma, Reduction of metastatic and angiogenic potency of malignant cancer by Eupatorium fortunei via suppression of MMP-9 activity and VEGF production, Scientific Reports 4, Article number:6994︱doi:10.1038/srep06994