Fumagillin inhibits colorectal cancer growth and metastasis in mice: In vivo and in vitro study of anti‐angiogenesis

Abstract

Fumagillin is an inhibitor of type 2 methionine aminopeptidase that can block blood vessel formation, but its molecular mechanism and therapeutic value in colon cancer still remain to be elucidated. In this study, male severe combined immunodeficiency (SCID) mice were injected with colon cancer cells in the subcutis and then treated with Fumagillin and Cyclo (Arg-Gly-Asp-D-Phe-Val), an integrin alphavbeta(3) antagonist. The tumor weight, microvessel density (MVD), and number of pulmonary metastatic foci were examined. Gene expression profiles were examined by microarray analysis of human umbilical endothelial cells (HUVEC). The Fumagillin-treated mice had smaller tumor mass, fewer pulmonary metastases, and lower MVD-CD105 levels than control animals. In vitro proliferation and tube formation of HUVEC was also significantly decreased by Fumagillin. Microarray analysis of Fumagillin-treated HUVEC showed upregulation of 71 genes and downregulation of 143 genes. Expression changes were involved in cell proliferation, migration, adhesion, and gene transcription. Quantitative real-time-polymerase chain reaction and western blotting showed decreased expression of cyclin E2, activated leukocyte cell adhesion molecule (ALCAM), and intercellular adhesion molecule-1 (ICAM-1) genes in the presence of Fumagillin. This downregulation by Fumagillin may be involved in the anti-angiogenesis by Fumagillin. In conclusion, Fumagillin was found to suppress colorectal cancer growth and metastasis by suppressing angiogenesis.

Local inhibition of angiogenesis results in an atrophic non-union in a rat osteotomy model

“…The in vitro experiments, aside from SU5416, confi rmed the inhibitory action of Fumagillin, Artesunate, and 3,5,4´-Trimethoxystilbene on endothelial cells. A similar dose-dependent negative effect on the proliferation had been described recently in different types of endothelial cells (Wang et al, 2000;Chen et al, 2004;Dell`Eva et al, 2004;Hou et al, 2009;Alex et al, 2010). The POB-like cells were less affected by adding either antiangiogenic substances.…”

Fumagillin, a Mycotoxin of Aspergillus fumigatus: Biosynthesis, Biological Activities, Detection, and Applications

“…It has been observed that in murine models of colorectal cancer, fumagillin and its derivative fr-11887 can inhibit colorectal growth and prevent metastasis [156,157]. On the other hand, it has also been demonstrated that the combination of fumagillin derivatives with antitumor molecules like 5-fluorouracil can inhibit the growth of colon adenocarcinoma tumor cell lines [158] or prolong its tumor growth inhibitory effect after the termination of treatment in an experimental murine model [159].…”

Preclinical and Clinical Perspective on Fungal Metabolites and Their Analogs as Anticancer Agents – From Bench to Bedside

“…Furthermore, fumagillin arrests endothelial cells in G1 phase of cell cycle along with suppression of cyclin E mRNA expression and protein level resulting in the inhibition of endothelial cell proliferation and motility. Microarray analysis of fumagillin-treated HUVEC shows an upregulation of 71 genes and downregulation of 143 genes that are mostly involved in cell proliferation, migration, adhesion, differentiation, and gene transcription [46]. Low dose of fumagillin treatment to SCID mice bearing colon cancer cells in the subcutis when harvested after 4 weeks of treatment had small tumor mass, fewer pulmonary metastases, and lower microvessel density relative to control group [46].…”

“…Microarray analysis of fumagillin-treated HUVEC shows an upregulation of 71 genes and downregulation of 143 genes that are mostly involved in cell proliferation, migration, adhesion, differentiation, and gene transcription [46]. Low dose of fumagillin treatment to SCID mice bearing colon cancer cells in the subcutis when harvested after 4 weeks of treatment had small tumor mass, fewer pulmonary metastases, and lower microvessel density relative to control group [46]. Suppression of hepatoma growth and metastasis by fumagillin has also been reported [47].…”