Takashi Sumida

Suppression of azoxymethane‐induced colon carcinogenesis in male F344 rats by mandarin juices rich in β‐cryptoxanthin and hesperidin

We have reported protective effects of dietary administration of a powder “CHRP” containing high amounts of β‐cryptoxanthin and hesperidin prepared from a Satsuma mandarin (Citrus unshiu Marc.) juice on azoxymethane (AOM)‐induced rat aberrant crypt foci through suppression of crypt cell proliferation and/or induction of detoxifying enzymes. In the present study, we investigated the modifying effects of a commercial Satsuma mandarin (Citrus unshiu Marc.) juice (MJ) and those of MJ2 and MJ5, which were prepared from MJ and are richer in β‐cryptoxanthin and hesperidin than MJ, on the occurrence of colonic tumors induced by AOM in male F344 rats. Rats were given 2 weekly s.c. injections of AOM (20 mg/kg body weight) to induce colonic neoplasms. They also received MJ, MJ2, or MJ5 as a drinking water at night for 36 weeks, starting 1 week after the last dosing of AOM. AOM exposure produced colonic adenocarcinoma with an incidence of 69% and a multiplicity of 0.76 ± 0.57/rat at week 38. MJ, MJ2, and MJ5 administration significantly reduced the frequency of colonic carcinoma [MJ: 35% (49% reduction), p < 0.02; MJ2: 20% (64% reduction), p = 0.0028; and MJ5: 15% (78% reduction), p < 0.00021] and multiplicity [MJ: 0.40 ± 0.58 (47% reduction), p < 0.05; MJ2: 0.25 ± 0.43 (67% reduction), p < 0.005; and MJ5: 0.15 ± 0.36 (80% reduction), p < 0.001]. Also, the numbers of cancer cells positive for proliferative cell nuclear antigen (PCNA) and cyclin D1 in colonic tumors were lowered by these treatments. In addition, treatment with MJ, MJ2, or MJ5 significantly increased apoptotic index in colonic adenocarcinoma. These findings might suggest effective chemopreventive ability of MJs, especially MJ5, in colon tumorigenesis. Int. J. Cancer 88:146–150, 2000.

Inhibitory effect of mandarin juice rich in β-cryptoxanthin and hesperidin on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced pulmonary tumorigenesis in mice

Previously we reported that a commercial Satsuma mandarin (Citrus unshiu Marc.) juice (MJ), MJ2 and MJ5, especially MJ5, effectively suppressed chemically-induced rat colon carcinogenesis (Int. J. Cancer 88 (2000) 146). MJ2 and MJ5 prepared from MJ have higher amounts of beta-cryptoxanthin and hesperidin than MJ, suggesting that principle chemopreventive factors in MJs may be beta-cryptoxanthin and hesperidin. Present study was conducted to test whether these MJs could modify carcinogenesis in other organ, lung initiated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in male A/J mice. Mice were given an intraperitoneal injection of NNK (10 micromol in saline/mouse) to induce pulmonary neoplasms. They also received MJ, MJ2 or MJ5 as a drinking water at night for 21 weeks, starting 1 week after the NNK injection. Treatments with MJ, MJ2, and MJ5 reduced the incidence of lung tumors and the inhibition by MJ5 (29% reduction) was statistically significant (P<0.05). MJs treatment lowered the multiplicity of lung neoplasms without statistical significance. Immunohistochemically, MJs, especially MJ5, reduced proliferating cell nuclear antigen (PCNA)-positive index in the lung tumors without affecting PCNA index in hyperplastic alveolar cell lesions. These findings might suggest that MJ5, which contain 3.9 mg beta-cryptoxanthin and 100 mg hesperidin in 100 g sample), has chemopreventive ability against NNK-induced mouse lung tumorigenesis.

Modifying effects of carotenoids on superoxide and nitric oxide generation from stimulated leukocytes

Excessive and prolonged generation of superoxide (O2-) and nitric oxide (NO) from inflammatory leukocytes is associated with several lifestyle-related diseases, including cancer. In the present study, we screened 19 natural carotenoids for their modifying effects on O2- and NO generation from differentiated human promyelocytic HL-60 cells and mouse macrophage RAW 264.7 cells, respectively. Of the carotenoids tested, halocynthiaxanthin, isolated from oysters, showed the highest suppressive effect on the generation of both free radicals. The inhibitory potencies of certain carotenoids on radical generation markedly exceeded that of beta-carotene. In addition, some important structural moieties regulating radical generation suppression are discussed.

Diet supplemented with citrus unshiu segment membrane suppresses chemically induced colonic preneoplastic lesions and fatty liver in male db/db mice

The modulatory effects of dietary citrus unshiu segment membrane (CUSM) on the occurrence of aberrant crypt foci (ACF) and β‐catenin accumulated crypts (BCACs) were determined in male C57BL/KsJ‐db/db (db/db) mice initiated with azoxymethane (AOM). Male db/db, db/+ and +/+ mice were given 5 weekly subcutaneous injections of AOM (15 mg/kg body weight), and then they were fed the diet containing 0.02%, 0.1% or 0.5% CUSM for 7 weeks. At Week 12, a significant increase in the numbers of ACF and BCAC was noted in the db/db mice in comparison with the db/+ and +/+ mice. Feeding with CUSM caused reduction in the frequency of ACF in all genotypes of mice and the potency was high in order of the db/db mice, db/+ mice and +/+ mice. The number of BCACs was also reduced by feeding with CUSM, thus resulting in a 28–61% reduction in the db/db mice, possibly due to suppression of cell proliferation activity in the lesions by feeding with CUSM‐containing diet. Clinical chemistry revealed a low serum level of triglyceride in mice fed CUSM. In addition, CUSM feeding inhibited fatty metamorphosis and fibrosis in the liver of db/db mice. Our findings show that CUSM in the diet has a chemopreventive ability against the early phase of AOM‐induced colon carcinogenesis in the db/db as well as db/+ and +/+ mice, indicating potential use of CUSM in cancer chemoprevention in obese people.

Effects of Oxygenated Carotenoid β-Cryptoxanthin on Morphological Differentiation and Apoptosis in Neuro2a Neuroblastoma Cells

Beta-Cryptoxanthin (βCx) was investigated for cell functions in neuroblastoma Neuro2a cells. The following results were obtained. 1. Beta-Cx induced neurite outgrowth. 2. Beta-Cx inhibited the etoposide-induced activation of caspase-3 activity in a dose-dependent manner. These data suggest a bioregulatry function of βCx in the control of differentiation and apoptosis in Neuro2a cells.