Effect of inositol hexaphosphate on the development of UVB-induced skin tumors in SKH1 hairless mice

Abstract

Inositol hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate that is abundant in many plants and in various high-fiber foods, such as cereals and legumes. IP6 has a striking, broad-spectrum anticancer activity in various in vitro and animal models, in which it interferes with key pathways in malignancy to inhibit cell proliferation, cell-cycle progression, metastasis, invasion, and angiogenesis and to induce apoptosis. In this study, we investigated the protective effects of IP6 in drinking water on the incidence of UVB-induced skin cancer in the SKH1 (Crl: SKH1-hr) mouse model. One group of 15 mice received 2% IP6 in drinking water and UVB exposure, and the other group (n = 15) received UVB exposure only. All mice in both groups were fed an IP6-deficient diet (AIN 76A). The treatment group started receiving 2% IP6 in the drinking water 3 d before irradiation. Mice were irradiated 3 times each week, starting at a dose of 1.5 kJ/m2, with weekly increases in increments of 1.5 kJ/m2 to a final dose of 7.5 kJ/m2. Tumor formation was monitored until the week 31. IP6 in drinking water significantly decreased tumor incidence by 5-fold and tumor multiplicity by 4-fold. These results show that IP6 has an antiphotocarcinogenic effect and can protect against UVB-induced tumor formation.

Figure 1.

Effect of UVB radiation in control mice, which had papillomatous skin tumors on their dorsums.

Figure 2.

Protective effects of 2% IP₆ against UVB-induced skin tumors in SKH1 hairless mice. (A) Tumor–mass incidence (proportion of mice bearing at least 1 tumor or mass). By week 31, the tumor incidence in the group treated with 2% IP₆ was 8.6% compared with 50% in the control group (P < 0.05). (B) Tumor multiplicity (average number of masses per mouse) was 2 in the mice treated with 2% IP₆ in drinking water compared with 8 in the control group.

Figure 3.

Histopathologic identification of different types of tumors and lesions in the control group. (A) Normal skin. B) Squamous cell carcinoma: tumors with papillomatous growth of epidermal cells and invasion of tumor cells into the dermis. (C) Cornifying epithelioma: concave proliferation of hyperplastic epidermis with thick keratin and neutrophilic exudate. (D) Epidermal hyperplasia: expansion of the epidermis due to increased keratinocyte proliferation. (E) Undifferentiated mesenchymal neoplasm (fibroma): undifferentiated stellate or spindle-shaped cells that are arranged loosely. For all panels, original magnification was ×10.

Figure 4.

Effect of IP₆ on UVB-induced carcinogenesis. Decreased percentage of preneoplastic lesions (epidermal hyperplasia) and other neoplasms (indicative of decreased tumor formation) in IP₆-treated group.

Figure 5.

NFκB expression in mouse skin tumors. (A) Tumor in IP₆-treated mice showing negative nuclear staining and only positive cytoplasmic staining in squamous keratinocytes.Original magnification, ×20 (B) Tumor in control mice showing positive nuclear staining (arrow). Original magnification, ×40.