The Prevention of a High Dose of Vitamin D or Its Combination with Sulforaphane on Intestinal Inflammation and Tumorigenesis in Apc^1638N Mice Fed a High‐Fat Diet

Abstract

Scope The previous study shows that obesity‐promoted inflammation is responsible for the activation of the intestinal tumorigenic Wnt‐signaling. The present study aims to test a dietary strategy, dietary supplementation with a high dose of vitamin D (VD) or its combination with sulforaphane (SFN) to inhibit intestinal inflammation and obesity‐associated tumorigenesis. Methods and results Apc1638N mice are randomly divided into four groups: LF, a low‐fat diet (10 kcal% fat) with 200 IU VD; HF, a high‐fat diet (60 kcal% fat) with 200 IU VD; HFD, a high‐fat diet with 5000 IU VD; and HFDS, a high‐fat diet plus 5000 IU VD and 0.23 g SFN per ≈4000 kcal. VD administration decreased tumor incidence and size, and the co‐administration with SFN (HFDS) magnified the effects. Inflammation and Wnt‐signaling are suppressed by VD. The addition of SFN decreased the activity of histone deacetylase (HDAC) and increased autophagy. Conclusion The administration of VD, at 5000 IU level, exerts an anti‐inflammatory property and leads to suppressed intestinal Wnt‐signaling and tumorigenesis in obese mice. The molecular function of SFN on a high dose of VD supplementation, although displayed on the inhibition of HDAC and the activation of autophagy, needs further investigation.

Dietary Fucoxanthin Induces Anoikis in Colorectal Adenocarcinoma by Suppressing Integrin Signaling in a Murine Colorectal Cancer Model

“…For instance, anchor-dependent cell aberration induces autophagy and entosis as well as anoikis [40,41]. Vitamin D and sulforaphane, functional lipids from food, enhance autophagy in small intestine tissue in APC 1638N mice given a high-fat diet [42]. Nintedanib, a tyrosine kinase inhibitor, is suggested to induce entosis in human prostate cancer cells in xenografted mice, along with E-cadherin upregulation and CDC42 downregulation [43].…”

Sulforaphane Combined with Vitamin D Induces Cytotoxicity Mediated by Oxidative Stress, DNA Damage, Autophagy, and JNK/MAPK Pathway Modulation in Human Prostate Tumor Cells

“…Vitamin D alone did not induce autophagy in DU145 and PC-3 cells, but it increased autophagy rates when combined with sulforaphane at 4 µM and 8 µM, respectively. The sulforaphane–vitamin D combination induces autophagy in the small intestine of mice [ 24 ]. Our findings suggested that vitamin D potentiated the effect of sulforaphane in inducing autophagy-associated cell death in DU145 and PC-3 cells.…”

“…Vitamin D combined with sulforaphane can modulate the WNT signaling pathway and inhibit histone deacetylases in Caco-2 colorectal cancer cells and TMX2–28 breast cancer cells [ 55 , 56 ]. This nutraceutical combination also induces autophagy in Apc1638N mice, which is heterozygous for germline mutation in the Apc gene and used to study intestinal tumorigenesis [ 24 ]. The findings of the present study with achievable plasma concentrations corroborate those described in the literature regarding the anticancer potential of sulforaphane and vitamin D in combination.…”

“…Administration of vitamin D combined with sulforaphane decreases the incidence and size of tumors in mice intestine, reduces histone deacetylase activity, and increases autophagy induction [ 24 ]. Sulforaphane and vitamin D alone are promising anticancer agents, but they have demonstrated low efficacy and bioavailability in clinical trials.…”

Association between histone deacetylase activity and vitamin D‐dependent gene expressions in relation to sulforaphane in human colorectal cancer cells

“…The two test groups are presented as without (−) and with (+) SFN since that is the only differing factor between HFD and HFDS dietary groups. Details of the sample collection and preservation are discussed elsewhere 19 …”