Low Molecular Weight Fucoidan Inhibits Tumor Angiogenesis through Downregulation of HIF-1/VEGF Signaling under Hypoxia

Abstract

Activation of hypoxia-induced hypoxia-inducible factors-1 (HIF-1) plays a critical role in promoting tumor angiogenesis, growth and metastasis. Low molecular weight fucoidan (LMWF) is prepared from brown algae, and exhibits anticancer activity. However, whether LMWF attenuates hypoxia-induced angiogenesis in bladder cancer cells and the molecular mechanisms involved remain unclear. This is the first study to demonstrate that LMWF can inhibit hypoxia-stimulated H2O2 formation, HIF-1 accumulation and transcriptional activity vascular endothelial growth factor (VEGF) secretion, and the migration and invasion in hypoxic human bladder cancer cells (T24) cells. LMWF also downregulated hypoxia-activated phosphorylation of PI3K/AKT/mTOR/p70S6K/4EBP-1 signaling in T24 cells. Blocking PI3K/AKT or mTOR activity strongly diminished hypoxia-induced HIF-1α expression and VEGF secretion in T24 cells, supporting the involvement of PI3K/AKT/mTOR in the induction of HIF-1α and VEGF. Additionally, LMWF significantly attenuated angiogenesis in vitro and in vivo evidenced by reduction of tube formation of hypoxic human umbilical vascular endothelial cells and blood capillary generation in the tumor. Similarly, administration of LMWF also inhibited the HIF-1α and VEGF expression in vivo, accompanied by a reduction of tumor growth. In summary, under hypoxia conditions, the antiangiogenic activity of LMWF in bladder cancer may be associated with suppressing HIF-1/VEGF-regulated signaling pathway.

Identification of a Pro-Angiogenic Potential and Cellular Uptake Mechanism of a LMW Highly Sulfated Fraction of Fucoidan from Ascophyllum nodosum

“…Chen et al showed that a low molecular weight fucoidan (LMWF) obtained from Sargassum hemiphyllum ( M w = 760 g/mol, 40% sulfate) dose-dependly reduced hypoxia effect on VEGF-induced capillary tube-like structure formation in Human Umbilical Endothelial Cells (HUVEC) in vitro, and did not affect angiogenesis under normoxic condition [33]. In addition, they showed that LMWF treatment inhibited the migration and invasion of hypoxic Human Bladder Cancer Cells (T24).…”

Silencing Prion Protein in HT29 Human Colorectal Cancer Cells Enhances Anticancer Response to Fucoidan

“…With respect to cancer therapy, fucoidan appears to be highly efficient in treating certain types of cancer, including breast, prostate and lung, as well as leukemia (10)(11)(12). Furthermore, fucoidan can also play a crucial role in inhibiting induced cancer signaling molecules, such as vascular endothelial growth factor (VEGF) (13,14). Although these results support the potential development of fucoidan as an anticancer drug, there is little information on the anticancer effect of fucoidan on colorectal cancer (CRC).…”

“…Several studies have demonstrated that fucoidan induces cancer cell death through mitochondrial abnormalities, including increased production of mitochondrial reactive oxygen species (21), inhibits tumor angiogenesis via down-regulation of HIF1 and VEGF (14), down-regulates cell cycle-regulated kinase (22)…”

Potencjał fukoidyny jako środka wspomagającego w terapii onkologicznej

“…Przeprowadzone dotychczas badania nad przeciwnowotworowymi właściwościami fukoidyny wykazały jej zdolność do hamowania angiogenezy w obrębie nowotworu [13,15,16,31,41]. Liu i wsp.…”

“…Badania prowadzone nad właściwościami fukoidyny pozyskanej z alg z gatunku Sargassum hemiphyllum wykazały jej zdolność do hamowania wzrostu guza i angiogenezy in vivo poprzez obniżanie aktywacji HIF-1α stymulowanej hipoksją, ekspresji VEGF i wewnątrzkomórkowego tworzenia reaktywnych form tlenu w komórkach raka pęcherza linii T24. Ponadto nie obserwowano spadku masy ciała zwierząt traktowanych fukoidyną, co świadczy o jej dobrej tolerancji [16].…”