Prostate cancer has the highest incidence rate among cancers in men. Unfortunately, as the number of patients with prostate cancer continues to increase, seeking treatment without side effects is essential. Previous studies have shown several ways to induce the anti-tumor effects using Fucoidan without side effects.

Hence, in this blog, I would like to share the survey that focuses on a different ant-cancer passway, “Anticancer Effect of Fucoidan on DU-145 Prostate Cancer Cells through Inhibition of PI3K/Akt and MAPK Pathway Expression” by Gang-Sik Choo et al. They established that PI3K/Akt signaling mediates the anticancer effects of Fucoidan on prostate cancer cells, including inhibition of proliferation.

The study measured cancer cell viability by MTT assay, and Fucoidan was administered to DU-145 prostate cancer and examined the effect. When DU-145 cells were treated with 0, 250, 500, 750, or 1000 μg/mL fucoidan for 24 hours, all were significantly reduced compared to the control group. (See Figure. 1)

Next, to investigate whether the suppression of DU-145 cell growth by Fucoidan is due to apoptosis, DU-145 prostate cancer cells were treated with 500 or 1000 μg/mL fucoidan and examined by staining and fluorescence microscopy.

An increase in cell-induced apoptosis was observed in the fucoidan-treated group. Consistent with the MTT assay, staining showed a decrease in the number of cancer cells in the fucoidan-treated compared with the control group. Similarly, Fucoidan increased cytoplasmic contraction and apoptotic body formation at 0, 500, and 1000 μg/mL fucoidan, respectively, compared to the control group. (See Figure. 2B) Higher concentrations of Fucoidan resulted in more significant apoptotic effects. These results suggest that Fucoidan killed DU-145 prostate cancer cells through the induction of apoptosis.

Fucoidan causes the formation of apoptotic complexes and activates caspases. So, they performed Western blot analysis to detect changes in the expression of Bcl-2 family proteins when DU-145 prostate cancer cells were treated with 500 or 1000 μg/mL fucoidan. Presentation of all pro-apoptotic proteins Bax, cleaved caspase-9, and cleaved PARP increased, whereas expression of the anti-apoptotic protein Bcl-2 decreased concentration-dependent. (See Figure. 3)

In general, the ERK signaling pathway is involved in cell proliferation, whereas JNK acts to antagonize cell proliferation. Therefore, we investigated how Fucoidan affects MAPK signaling in DU-145 prostate cancer cells. Treatment of DU-145 prostate cancer cells with 500 or 1000 μg/mL fucoidan for 24 h did not change the phosphorylation of JNK. However, it decreased ERK and p38 in a concentration-dependent manner. (See Figure 4B)

Akt, also known as protein kinase B, is a serine/threonine kinase activated by PI3K and regulates many biological responses, including cell proliferation, differentiation, and cell cycle-related survival. When triggered by PI3K, Akt inhibits apoptosis by inhibiting BAD (Bcl-2-associated death promoter) or caspase-9 expression. So, then western blotting was performed to examine the effects of Fucoidan on the PI3K/Akt signaling pathway. Treatment of DU-145 prostate cancer cells with 500 or 1000 μg/mL fucoidan for 24 hours decreased the phosphorylation of Akt and PI3K in a concentration-dependent manner. The study showed that Fucoidan induces apoptosis in DU-145 prostate cancer cells by reducing Akt and PI3K activation.

Immunohistochemical assays were utilized to measure the activation (phosphorylation) of Akt and ERK in tumor tissue harvested from human tumor xenograft mice after intraperitoneal injection of 5 or 10 mg/kg fucoidan. Both doses of Fucoidan were observed to decrease phosphorylation of Akt and ERK compared to controls. Hence, Fucoidan inhibits tumor growth and migration by modulating Akt and ERK activity.

Subsequently, liver and kidney tissues of tumor-xenografted mice were examined histologically by hematoxylin and eosin staining, followed by fluorescence microscopy to assess fucoidan-induced organ toxicity. No histopathological abnormalities were detected, indicating that Fucoidan does not cause detectable toxic effects.

In conclusion, Fucoidan treatment was found to reduce p-Akt and p-ERK levels, indicating that apoptosis in DU-145 prostate cancer cells resulted from the regulation of PI3K/Akt and MAPK signaling pathways. Thus, the study provides a molecular basis for using Fucoidan as a cancer chemopreventive and chemotherapeutic agent.

Source: Mar Drugs. 2016 Jul; 14(7): 126  doi: 10.3390/md14070126