Another incredible research article showcasing one of Infinimin® Multivitamin compounds (fucoidan) and its unique anticancer activity! More research is needed in humans, but another great step forward!!

Marine organisms are sources of several natural compounds with potential clinical use. However, only a few marine‐based pharmaceuticals have been approved for use due to limited knowledge on their biological activities. Here, we identified the functional role of fucoidan extracted from Fucus vesiculosous on ovarian cancer. Fucoidan increased the death of ES‐2 and OV‐90 cells, through a reduction in proliferation, cell cycle arrest, releases of cytochrome c, reactive oxygen species (ROS) generation, and endoplasmic reticulum (ER) stress.

Additionally, fucoidan increased the concentration of cytosolic and mitochondrial calcium in both cells. The decrease of cell proliferation was controlled by the inactivation of PI3K and MAPK signaling cascades in ES‐2 and OV‐90 cells. In a toxicity assay with normal zebrafish larvae, fucoidan did not induce toxicity, cardiotoxicity, development, kinesis, and apoptosis at different concentrations.

However, it disrupted tumor formation and vascular development in a zebrafish xenograft model and angiogenesis transgenic (Tg, fli1‐eGFP) model, respectively.

To validate the toxic effect of fucoidan, we performed toxicity assay of the response of normal zebrafish embryos to fucoidan (Figure 7A). Fucoidan did not induce toxicity, cardiotoxicity, and kinesis in the zebrafish embryos. Although their development was slightly decreased, there was no significant efficacy of fucoidan on the development of the embryos. To determine the effects of fucoidan on apoptosis in vivo, the zebrafish embryos were incubated with fucoidan and the apoptotic cells were tagged with acridine orange (Figure 7B). Our results showed that the apoptotic cells indicated by green fluorescence within the embryos were rarely detected in fucoidan‐treated zebrafish. Although the expression of apoptosis‐related genes including casp8 and casp9 decreased in 300 μg/mL fucoidan‐treated zebrafish as indicated by quantitative RT‐PCR analysis, there was no difference in the expression of casp3 and p53 genes in comparison with the control (Figure 7C–F). There was an efficient suppression of tumor volume and formation in fucoidan‐treated transgenic model compared with the vehicle‐treated model (Figure 7G,H).

To identify if fucoidan has anti‐angiogenic effects, we used the zebrafish Tg(fli1:eGFP) line generated for the study of vascular system. Treatment with fucoidan (300 μg/mL) disrupted the vascular development of zebrafish embryo, especially dorsal longitudinal anastomotic vessel (DLAV), intersegmental vessel (ISV), and dorsal aorta (DA) parts compared with vehicle‐treated fli1 Tg models (Figure 8A). In accordance with the results, the angiogenesis‐related genes such as vascular endothelial growth factor Aa (vegfaa), vegfc, fms related tyrosine kinase 1 (flt1), flt4, kinase insert domain receptor (kdr), and kdr like (kdrl) were dramatically decreased in fucoidan‐incubated fli1 Tg zebrafish compared with the control (Figure 8B–G). Next, we compared the anti‐angiogenic effects of fucoidan with conventional anti‐cancer drugs including cisplatin and paclitaxel in human ovarian cancer cell lines. The mRNA expression of VEGFs (VEGFA‐VEGFD) was reduced by fucoidan in ES‐2 and OV‐ 90 cells (Figure 8H–K). Their expression was synergistically decreased by a combination of fucoidan with cisplatin or paclitaxel compared with individual treatment. Even though the synergy of fucoidan with cisplatin or paclitaxel on FLT1 expression was indicated only in ES‐2 cells, mRNA expression of FLT4 and KDR was highly inhibited in ES‐2 and OV‐90 cells incubated with the combined treatment compared with those incubated with the individual treatments (Figure 8L–N).

Fucoidan caused a 40% growth inhibition in ES‐2 and OV‐90 cells at a dose of 300 μg/mL, and it induced the apoptosis in ovarian cancer cells after 48 h incubation. Additionally, fucoidan triggered the depolarization of MMP, production of ROS, and an increase in calcium ion concentration in cytosol and mitochondria. Fucoidan inhibited PI3K/MAPK intracellular signal pathways; however, it activated the apoptotic cascades and ER stress sensor proteins in the ovarian cancer cells as illustrated in Figure 9. Although fucoidan did not affect the normal zebrafish in vivo, it highly decreased tumor formation and angiogenesis in the xenograft and fli1 Tg models, respectively. Additionally, fucoidan suppressed the expression of angiogenesis‐related genes in vivo and in vitro by enhancing the efficiency of chemotherapeutic agents. These data indicate that fucoidan can be used as a novel drug for the management and treatment of ovarian cancer.

Collectively, the results indicate that fucoidan may be a novel pharmaceutical for the management of human ovarian cancer.

Again, another incredible research article showcasing one of Infinimin® Multivitamin compounds (fucoidan) and its unique anticancer activity! More research is needed in humans, but another great step forward!!

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References

1. Hyocheol Bae, et. al. Fucoidan Derived from Fucus vesiculosus Inhibits the Development of Human Ovarian Cancer. Marine Drugs. January 9, 2020.