Sweet orange (Citrus sinensis L.) peel is a rich source of flavonoids, especially polymethoxyflavones. Polymethoxyflavones are almost exclusively found in citrus fruits, particularly in the peels of sweet oranges and mandarins, and have been shown to have antiproliferative and proapoptotic effects in cancer cells. Previously, it was shown that individual polymethoxyflavones from orange peel induce Ca(2+)-mediated apoptosis in human breast cancer cells. In the current study the authors report that orange peel extract fractions (1) containing a mixture of non-hydroxylated polymethoxyflavones and hydroxylated polymethoxyflavones; and (2) containing only hydroxylated polymethoxyflavones both inhibited growth and induced apoptosis in breast cancer cells.

The current case-control study was designed to compare the diets of a group of Korean breast cancer patients with a healthy control group. The cases included 97 women with newly confirmed diagnoses of breast cancer at the inpatient or outpatient clinic of Yeouido St. Mary’s Hospital in Seoul, and excluded women with any history of liver diseases, diabetes mellitus, respiratory disorders and cardiovascular diseases. The 97-person control group also excluded women with known malignant, hormonal, gynecological or endocrine diseases. Intake of nutrients in 117 food items were estimated in the breast cancer patients and age-matched healthy controls using a quantitative food frequency questionnaire administered by a trained dietitian. The questionnaire also included general information (age, sex and marital status), age at menarche, and pregnancy history. It was found that the average caloric intake of the breast cancer patients and the healthy controls did not differ significantly. However, the breast cancer patients consumed significantly less fat and antioxidant nutrients such as vitamin A, retinol, beta-carotene, vitamin C and vitamin E than did the controls. Consumption of eggs (p<0.01), legumes (p<0.05), vegetables (p<0.05), seasonings (p<0.001), and oils and fats (p<0.01) was significantly lower in the breast cancer patients. However, the level of energy from fat is relatively low in Korean patients compared to their Western counterparts, and fat consumption may not be an independent risk factor at this level of intake. With respect to particular foods, in addition to eggs, the breast cancer patients consumed a significantly lower quantity of bean curd (tofu), onion, garlic, green pepper, sweet pepper, kale, cucumber, seasoned bean sprouts, sesame leaf, zucchini, radish, mushroom, crown daisy, red pepper paste, bean paste, spicy bean paste, orange juice, grape juice, and tomato juice than the controls. On the other hand, the breast cancer patients consumed significantly greater quantities of cooked rice, noodles, deep fried chicken, satsuma mandarin, Korean melon, kimchi and coffee than the controls. The authors conclude that since the breast cancer patients consumed less soy and vegetables, they had a lower intake than the controls of rich sources of antioxidant nutrients, phytosterols, fiber and non-nutritional components that may reduce the risk of cancer. In addition, the breast cancer patients in this study consumed lower quantities of red pepper paste, bean paste and spicy bean paste, causing their intake of pepper flavonols (which may have a protective effect on breast cancer risk) to be lower than that of the controls.

Orange peel extract is an excellent source of polymethoxyflavones with potential chemopreventive properties. The orange peel extract used in the present study was a mixture containing tangeretin, heptamethoxyflavone, tetramethoxyflavone, nobiletin, hexamethoxyflavone, and sinensitin. C57Bl/6 mice were fed a new “Western-style” diet, which had previously induced atypical hyperplasias in mammary gland, and the Western-style diet supplemented with the standardized orange peel extract containing 30% polymethoxyflavones. The mice were divided into four groups depending on the diets they were fed: (1) control diet; (2) Western-style diet; (3) 0.25% orange peel extract in Western-style diet; or (4) 0.5 % orange peel extract in Western-style diet. After three months, atypical hyperplasias developed in the mammary glands of mice fed the Western-style diet, but not in controls. The mice fed with orange peel extract in Western-style diet developed less atypical hyperplasias per mouse decreased compared to those receiving the feeding Western-style diet alone. Apoptosis increased in the orange peel extract-treated groups with no inhibition of mitosis.

Limonoids are highly oxidized triterpenes present in Rutaceae and Maliaceae families. Experiments using laboratory animals and human breast cancer cells have demonstrated that citrus limonoids may have substantial chemopreventive properties. The compounds have been shown to be free of toxic effects in animal models, so potential exists for the use of limonoids against human cancer.

To evaluate if orange juice could reduce DNA damage induced by two alkylating agents, methyl methanesulfonate (MMS) and cyclophosphamide (CP), mice were treated orally with MMS and CP before and after treatment with orange juice. The orange juice treatment was found to reduce the extent of DNA damage caused by both mutagens. In the case of MMS, the effect of orange juice was both protective (orange juice pre-treatment) and reparative (orange juice post-treatment); for CP, the effect was solely reparative. Given that MMS and CP have different mechanisms of the action, different protective effects are suggested. The authors conclude that orange juice is capable of in vivo modulation of MMS and CP mutagenicity.

Previous studies have demonstrated that hesperidin, a flavanone glycoside in orange juice, inhibits colon carcinogenesis and that feeding susceptible rates with double-strength orange juice delays the onset of chemically induced mammary cancer. The current study tested whether feeding single-strength, pasteurized orange juice would inhibit azoxymethane (AOM)-induced colon cancer in male Fischer 344 rats. Colon cancer was initiated by injecting AOM. Feeding orange juice reduced tumor incidence and the proliferation zone in the colonic mucosa. The authors concluded that hesperidin, other flavonoids, limonin 17-b-D-glucopyranoside, and other limonoid glucosides are potential chemopreventive agents in orange juice.

The present case-control study was designed to examine the associations between food and beverage consumption and the development of breast cancer in men. The study, which was conducted between 1983 and 1986, included 200 male breast cancer cases, which were found using 10 population-based cancer registries. A total of 291 controls were selected by random-digit dialing (< age 65) and Medicare beneficiary lists (> or = age 65). The only trend found with increasing intakes of specific foods was an increase in breast cancer risk with consumption of citrus fruits. Similarly, no increase in risk with increasing amounts of specific fats, vitamins, or minerals, or with protein, fiber, carbohydrate, starches, nitrites, or alcohol consumed was found, except for an increase in risk associated with dietary vitamin C consumption. However, a decreasing trend in risk with dietary niacin and with coffee, and an increasing trend in risk with tea consumption were seen. No associations were found between risk of breast cancer and use of any dietary supplements, including vitamin C. The authors comment that the study findings are inconsistent with those from studies of breast cancer in women and probably do not represent causal relationships. Furthermore, they conclude that dietary factors are unlikely to be strong determinants of breast cancer in men.

Two citrus flavonoids, hesperetin and naringenin, found in oranges and grapefruit, respectively, and four noncitrus flavonoids, baicalein, galangin, genistein, and quercetin, were tested singly and in one-to-one combinations for their effects on proliferation and growth of a human breast carcinoma cell line, MDA-MB-435. The concentration at which cell proliferation was inhibited by 50% (IC50), based on incorporation of [3H]thymidine, varied from 5.9 to 140 micrograms/ml for the single flavonoids, with the most potent being baicalein. IC50 values for the one-to-one combinations ranged from 4.7 micrograms/ml (quercetin + hesperetin, quercetin + naringenin) to 22.5 micrograms/ml (naringenin + hesperetin). All the flavonoids showed low cytotoxicity (> 500 micrograms/ml for 50% cell death). Naringenin is present in grapefruit mainly as its glycosylated form, naringin. These compounds, as well as grapefruit and orange juice concentrates, were tested for their ability to inhibit development of mammary tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female Sprague-Dawley rats. Two experiments were conducted in which groups of 21 rats were fed a semipurified diet containing 5% corn oil and were given a 5-mg dose of DMBA intragastrically at approximately 50 days of age while in diestrus. One week later, individual groups were given double-strength grapefruit juice or orange juice or fed naringin or naringenin at levels comparable to that provided by the grapefruit juice; in the second experiment, the rats were fed a semipurified diet containing 20% corn oil at that time. As expected, rats fed the high-fat diet developed more tumors than rats fed the low-fat diet, but in both experiments tumor development was delayed in the groups given orange juice or fed the naringin-supplemented diet compared with the other three groups. Although tumor incidence and tumor burden (grams of tumor/rat) were somewhat variable in the different groups, rats given orange juice had a smaller tumor burden than controls, although they grew better than any of the other groups. These experiments provide evidence of anticancer properties of orange juice and indicate that citrus flavonoids are effective inhibitors of human breast cancer cell proliferation in vitro, especially when paired with quercetin, which is widely distributed in other foods.