Docetaxel, paclitaxel, and cabazitaxel are taxane-based chemotherapies that are commonly used in cancer treatment, but despite their effectiveness, cancer cells tend to develop resistance to these drugs over time, ultimately leading to reduced cancer survival rates and increased chances of recurrence. By inhibiting the function of microtubules, Docetaxel effectively disrupts the process of cell division and leads to the destruction of cancer cells. One of the indications to look out for is prostate cancer.

Prostate cancer (PCa) cases have the potential to progress and develop into castration-resistant prostate cancer (CRPCa) as well as metastatic CRPCa (mCRPCa). Docetaxel has been administered to patients with CRPCa and mCRPCa. However, the emergence of docetaxel resistance after six months of treatment has become a pressing clinical concern for patients with CRPCa and mCRPCa. Hence, in this blog, I would like to share Chang-Hsun Ho et al.’s study “Active Targeting of P-Selectin by Fucoidan Modulates the Molecular Profiling of Metastasis in Docetaxel-Resistant Prostate Cancer.”

According to the study, it has been demonstrated that the bioactivity of fucoidan plays a significant role in docetaxel-resistant PCa cells. It achieves this by inhibiting IL-1R through its binding to P-selectin and also by inhibiting the expression levels of NF-κB p50 and Cox2 in this particular metastasis-suppressive signaling pathway. In addition, the research found that the combination treatment of fucoidan and docetaxel exhibited significantly anticancer and synergistic effects on the viability of DU/DX50 cells, which overcomes the current limitations and associated with improving treatment outcomes. In general, the combination of fucoidan and chemotherapy has the potential to produce positive outcomes and assist in the management of docetaxel-resistant prostate cancer.

In order to evaluate the migration and invasion capabilities of both the parental PCa cells and the docetaxel-resistant PCa cells, a Transwell assay to measure the rates of migration and invasion was conducted. Specifically, the study focused on examining the migration and invasion rates in the PCa cell line DU145, as well as in the 50 nM docetaxel-resistant DU/DX50 cells. The quantified results show that the number of migrated DU/DX50 cells is significantly higher than DU145 cells. In order to confirm the drug resistance status, the expression levels of the drug efflux protein family (ABCC1 and ABCB1) and P-selectin were examined in DU/DX50 cells through Western blotting. This data revealed that the level of ABCB1 in DU/DX50 cells was over 40 times higher than the level of ABCB1 in DU145 cells. Moreover, the DU/DX50 cells exhibited an overexpression of P-selectin, while there was a slight increase in ABCC1 expression, as illustrated in Figure 1B. These data indicate that DU/DX50 cells possess high migration and drug resistance abilities.

Furthermore, the evaluation of the migration and invasion ability of docetaxel-resistant DU/DX50 cells was conducted in the presence of fucoidan. It was observed that there was a notable decrease in the number of migrating cells when treated with fucoidan at concentrations ranging from 0.1 mg/mL to 0.2 mg/mL. Therefore, fucoidan treatment significantly reduced the migration and invasion of docetaxel-resistant PCa cells in a concentration-dependent manner, as shown in Figure 3.

In fucoidan-treated DU/DX50 cells, fucoidan interacted with P-selectin, induced downregulation of IL-1R, and caused a decrease in IKKα expression. In contrast, the depletion of IKKα caused a decline in Cox2 expression by suppressing IκBα phosphorylation, deactivating NFκB, and obstructing this signaling pathway, impeding metastasis. Western blotting was performed to verify the expression levels of transferred proteins obtained from a microwave array (MWA). The findings indicate that, as the concentration of fucoidan increases, the expression levels of IL-1R, IKKα, NF-κB p50, and Cox2 decrease.

They estimated the potential inhibitory effect of fucoidan or docetaxel alone and analyzed the synergistic effect of fucoidan/docetaxel combination treatment on the survival rate of docetaxel-resistant PCa cells. The drugs exhibited the ability to inhibit cell proliferation on their own, and this inhibition was dependent on the concentration. On the other hand, fucoidan and docetaxel showed inhibition only at specific concentrations, 0.8 mg/mL and 320.0 ng/mL respectively. Additionally, the maximum inhibitory concentration (IC30) for DU/DX50 cells was found to be 30%. The anticancer efficacy of fucoidan/docetaxel as a combination therapy was compared by combining docetaxel at concentrations of 160 ng/mL or 320 ng/mL with fucoidan at various concentrations (ranging from 0.0 to 0.6 mg/mL). Cell viability decreased with each concentration of docetaxel. Fucoidan/docetaxel treatment had a strong synergistic effect on cell viability, and a change in the combination index (CI) value was observed when combined with fucoidan at a fixed docetaxel concentration of 160 ng/mL.

The motility of docetaxel-resistant DU/DX50 cells was observed to be reduced in this study through the administration of fucoidan. This reduction was attributed to the binding of fucoidan to P-selectin, causing a decrease in its expression. Consequently, the downregulation of IL-1R occurred, leading to the inactivation of NF-κB and resulting in a decrease in Cox2 expression. The study also observed a synergistic effect of fucoidan and docetaxel on the viability of docetaxel-resistant PCa cells. In conclusion, Fucoidan can be expected to be effective against chemotherapy.

Source: Mar. Drugs 2022, 20(9), 542; https://doi.org/10.3390/md20090542