Fucoxanthin (Fx), abundantly contained in edible brown algae, is a carotenoid with strong anti-cancer potential. Anoikis is an anchor-dependent apoptosis particularly related to integrin signaling, and a target for cancer preventive strategies. We recently demonstrated that Fx prevented colon cancer in azoxymethane-dextrane sodium sulfate (AOM/DSS) carcinogenic model mice, and that it increased anoikis-like integrin β1^low/-/cleaved caspase-3^high cells in colonic mucosal crypts. However, an induction mechanism of anoikis by Fx in adenocarcinoma tissue remains unresolved. Thus, we investigated anoikis in colonic adenocarcinoma in AOM/DSS mice. Fx administration (30 mg/kg body weight) significantly suppressed the incidence and multiplicity of colonic adenocarcinoma in AOM/DSS mice. A number of anoikis-like integrin β1^low/-/cleaved caspase-3^high cells in colonic adenocarcinoma and mucosal crypts were significantly increased, 8.3- and 3.5-fold in the Fx group compared with those of the control group, respectively. The results indicated the increase of anoikis-like cells occurred more strongly in colonic adenocarcinoma than in colonic mucosal crypts. In addition, integrin β1 expression, and pFAK (Tyr³⁹⁷) and pPaxillin (Tyr³¹) activation in mucosal tissue decreased 0.7-, 0.5- and 0.6-fold by Fx administration, respectively. The results suggest that Fx induces anoikis in colonic adenocarcinoma developed by AOM/DSS treatment through attenuation of integrin signaling.

Colorectal cancer (CRC), which ranks among the top 10 most prevalent cancers, can obtain a good outcome with appropriate surgery and/or chemotherapy. However, the global numbers of both new cancer cases and death from CRC are expected to increase up to 2030. Diet-induced lifestyle modification is suggested to be effective in reducing the risk of human CRC; therefore, interventional studies using diets or diet-derived compounds have been conducted to explore the prevention of CRC. Fucoxanthin (Fx), a dietary carotenoid, is predominantly contained in edible brown algae, such as Undaria pinnatifida (wakame) and Himanthalia elongata (Sea spaghetti), which are consumed particularly frequently in Asian countries but also in some Western countries. Fx is responsible for a majority of the anticancer effects exerted by the lipophilic bioactive compounds in those algae. Interventional human trials have shown that Fx and brown algae mitigate certain risk factors for CRC; however, the direct mechanisms underlying the anti-CRC properties of Fx remain elusive. Fx and its deacetylated type “fucoxanthinol” (FxOH) have been reported to exert potential anticancer effects in preclinical cancer models through the suppression of many cancer-related signal pathways and the tumor microenvironment or alteration of the gut microbiota. We herein review the most recent studies on Fx as a potential candidate drug for CRC prevention.

Benzotriazole UV stabilizers (BUVSs) are widely used as additives in various materials, including plastics, to prevent damage from UV-irradiation. However, despite the extensive usage of BUVSs, information on their toxicological properties is limited. In this study, we investigated the effect of BUVSs on the immune regulatory system via the aryl hydrocarbon receptor (AhR). A cell-based transactivation assay using DR-EcoScreen cells revealed that, among 13 BUVSs tested, UV-P, UV-PS, UV-9, and UV-090 activated AhR in a dose-dependent manner. In particular, the AhR agonistic activity of UV-PS was about 10-fold more potent than those of UV-P, UV-090, and UV-9, and UV-PS acted as a full agonist against AhR. In order to investigate the immune regulatory effects of these BUVSs, we orally treated C57BL/6 mice with UV-PS or UV-P (10, 30, and 100 mg/kg) and studied the differentiation of regulatory T cells (Tregs) in spleen cells. Flow-cytometry analysis revealed that the administration of UV-PS (30 and 100 mg/kg) or UV-P (100 mg/kg) significantly increased the population of CD4⁺-/CD25⁺-/Foxp3⁺ Tregs in the spleen. In addition, we found that the in vitro exposure of mouse splenocytes to UV-PS (10 and 30 μM) or UV-P (30 μM) as well as to TCDD (0.1 nM) significantly induced Tregs. Notably, the induction of Tregs was eliminated by co-treatment with an AhR antagonist, CH-223191, in each case. Taken together, these findings suggest that some BUVSs might induce Tregs through direct AhR activation and act as immunosuppressive modulators.

In this study, we used reporter gene assays in COS-1 cells to examine the activation of rat pregnane X receptor (PXR), rat constitutive androstane receptor (CAR) and rat peroxisome-proliferator activated receptor (PPAR)α by pyrethroid pesticides, and to understand the effects of metabolic modification on their activities. All eight pyrethroids tested in this study showed rat PXR agonistic activity; deltamethrin was the most potent, followed by cis-permethrin and cypermethrin. However, when the pyrethroids were incubated with rat liver microsomes, their rat PXR activities were decreased to various extents. Cis- and trans-permethrin showed weak rat CAR agonistic activity, while the other pyrethroids were inactive. However, fenvalerate showed dose-dependent inverse agonistic activity toward rat CAR, and this activity was reduced after metabolism. None of the pyrethroids showed rat PPARα agonistic activity, but a metabolite of cis-/trans-permethrin and phenothrin, 3-phenoxybenzoic acid, activated rat PPARα. Since PXR, CAR and PPARα regulate various xenobiotic/endobiotic-metabolizing enzymes, activation of these receptors by pyrethroids may result in endocrine disruption due to changes of hormone-metabolizing activities.