Cranberry phytochemical extracts induce cell cycle arrest and apoptosis in human MCF-7 breast cancer cells
Introduction
Breast cancer is the most commonly diagnosed invasive cancer in women in the US and is one of the leading causes of death due to cancer [1]. Breast cancer is extremely difficult to treat due to several distinct classes of tumors that exhibit different treatment response [2]. The non-steroidal anti-estrogen medicine, Tamoxifen, has been reported to be effective in only one-third of the breast cancer patients [3]. Thus, searching for new alternative agents for the prevention and treatment of breast cancer is in great need.
An alternative strategy to lower the risk of cancer is through the dietary modification. It has been suggested that one-third of all cancer deaths could be avoided through this approach [4], [5]. Epidemiological studies have consistently shown that increased consumption of fruits and vegetables is associated with reduced risk of developing cancer [6], [7]. It has been suggested that phytochemicals of fruits and vegetables are primary contributors to these health benefits of fruits and vegetables in the prevention of cancers [8], [9], [10]. Direct associations between increased consumption of fruits and vegetables and decreased risk of breast cancer have been observed in several studies [2], [11], [12]. In a review focusing on the survival of breast cancer patients and their intake of fruits and vegetables, five of the eight cohort studies showed an inverse relationship between vegetable and fruit intake and survival of breast cancer patient, with a 20–90% reduction in death risk [13].
Two major antioxidants, vitamin C and β-carotene, have long been thought to be key components responsible for the chemopreventative effects of fruits and vegetables [14], [15], [16]. Much research has been devoted to identifying the key components and mechanisms that contribute to the health benefits of cranberries [17], [18]. However, increasing evidence suggested that these key factors are much more complex in scope, interaction and magnitude than what current research approaches commonly recognize. Increasingly, recent research suggests that the health benefits of fruits and vegetables are due to the additive and synergistic effects of multiple phytochemicals, rather than to a single source, such as vitamin C or β-carotene [8]. Single compounds or supplement pills simply could not mimic the health benefits provided by the complex of over 8000 different phytochemicals in foods. We have proposed that the benefit of a diet rich in fruit and vegetables is attributed to the complex mixture of phytochemicals present in whole foods, which could not be substituted by single compounds or supplement pills [19].
The bioactivity and mechanism of cranberries against urinary tract infections have been extensively studied and well documented [20]. Cranberry juice has been reported to inhibit copper-induced low-density lipoprotein (LDL) oxidation [21], [22]. In previous studies, we demonstrated that cranberries contained abundant phenolic compounds and possessed the highest level of antioxidant activity among the commonly consumed fruits and vegetables tested [23], [24]. Much research has associated dietary antioxidants with prevention of cancer [25], [26], and a high plasma antioxidant level has been positively associated with a lowered risk of breast cancer [27]. Cranberries are abundant in antioxidants; however, there is little available research on the effects and mechanisms of cranberries on the prevention of breast cancer.
Induction of apoptosis and inhibition of tumor cell proliferation have been used as markers for evaluation of phytochemical anti-cancer activities [28], [29], [30], and many chemotherapy agents exert their effects by interruption of cell cycle progression or by induction of apoptosis in cancer cells. An imbalance between cell proliferation and apoptosis has been implicated in breast cancer development [31]. The cell cycle is simply the program for cell growth and cell proliferation. Thus, cell cycle modulation could serve as an effective method in the regulation of cell proliferation. Several typical events of early cell-cycle regulation are also associated with apoptosis [32]. The growth inhibition of human breast cancer MCF-7 cells by resveratrol could be partially explained by the bioactive effects of this intensively studied phytochemical on cell-cycle control and apoptosis induction [33]. Recently, we demonstrated that cranberry extracts exhibited potent anti-proliferative activity towards human liver cancer HepG2 cells [23] and human colon cancer Caco-2 cells (data not published). The objective of the present study was to determine: (1) if cranberry extracts could inhibit human breast cancer MCF-7 cell proliferation; (2) if the exhibited anti-proliferative activity of cranberry extracts is associated with cell-cycle regulation and apoptosis induction.
Section snippets
Chemicals
Aluminum chloride, sodium hydroxide, methyl tert-butyl ether, methanol and acetone were purchased from Fisher Scientific (Pittsburgh, PA). Gallic acid and metaphosphoric acid was obtained from ICN Biomedical Inc. (Costa Mesa, CA). Sodium nitrite, (+)-catechin, Folin–Ciocalteu reagent, hydrochloric acid, propidium iodide, methyl green, and Triton X-100 were purchased from Sigma Chemical Company (St Louis, MO). All reagents used in the study were of analytical grade.
Preparation of cranberry extracts
Cranberries of the Early Black
Results
Total amounts of major phytochemicals, phenolics, flavonoids and anthocyanins, in cranberry extracts were quantified. The total phenolic content of cranberry extracts was 570.4±21.1 mg gallic acid equivalents/100 g fresh cranberries. The total flavonoid content of cranberry extracts was 161.6±20.3 mg of catechin equivalents/100 g fresh cranberries. Total monomeric anthocyanins of cranberry extracts was 92.0±4.2 mg of cyaniding-3-glucoside equivalent/100 g fresh cranberries.
The anti-proliferative
Discussion
Epidemiological studies have consistently shown that the consumption of fruits and vegetables reduce the risk of developing cancers [7], [39]. In a report reviewing 12 major case–control studies of breast cancer, a significant inverse association was observed between fruit and vegetable intake and breast cancer risk [14]. Vitamin C and β-carotene are extensively used as markers of fruit and vegetable intake. However, vitamin C supplementation showed no effects on prevention of cancer and
References (55)
- et al.
Dietary agents in cancer prevention: flavonoids and isoflavonoids
Pharmacol. Ther.
(2001) - et al.
Screening of selected flavonoids and phenolic acids in 19 berries
Food Res. Int.
(1999) Potential synergy of phytochemicals in cancer prevention: mechanism of action
J. Nutr.
(2004)- et al.
Cranberry extract inhibits low density lipoprotein oxidation
Life Sci.
(1998) - et al.
Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by isoprenoids
J. Nutr.
(1999) - et al.
Analysis of total phenols and other oxidation substrates and antioxidants by means of folin–ciocalteu reagent
Method Enzymol.
(1999) Molecular mechanism of chemopreventive effects of selected dietary and medicinal phenolic substances
Mutat. Res.
(1999)- ACS Cancer Statistics 2004, A presentation from the American Cancer Society (Ed.), American Cancer Society Inc.,...
- et al.
Breast cancer and prostate cancer: an analysis of common epidemiological, genetic, and biochemical features
Endocr. Rev.
(1998) The control of breast cancer: the role of tamoxifen
Semin. Oncol.
(1997)
Diet, nutrition, and avoidable cancer
Environ. Health Perspect.
Avoidable risks of cancer in the United States
J. Natl Cancer Inst.
Recent advances in chemoprevention of cancer
Science
Fruit, vegetables, and cancer prevention—a review of the epidemiologic evidence
Nutr. Cancer Int. J.
Health benefits of fruit and vegetables are from aditive and synergistic combinations of phytochemicals
Am. J. Clin. Nutr.
Quercetin and rutin as inhibitors of azoxymethanol-induced colonic neoplasia
Carcinogenesis
Total antioxidant capacity of fruits
J. Agric. Food Chem.
Premenopausal breast cancer risk and intake of vegetables, fruits, and related nutrients
J. Natl Cancer Inst.
Nutrition and survival after the diagnosis of breast cancer: a review of the evidence
J. Clin. Oncol.
Dietary factors and risk of breast cancer: combined analysis of 12 case-control studies
J. Natl Cancer Inst.
Increased dietary carotene intake and lowered cancer deaths in an elderly population
Am. J. Epidemiol.
Vitamin C and cancer prevention—the epidemiologic evidence
Am. J. Clin. Nutr.
Composition of a chemopreventive proanthocyanidin-rich fraction from cranberry fruits responsible for the inhibition of 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) activity
J. Agric. Food Chem.
Cranberry proanthocyanidins and the maintenance of urinary tract health
Crit. Rev. Food Sci. Nutr.
Cranberry flavonoids, atherosclerosis and cardiovascular health
Crit. Rev. Food Sci. Nutr.
Antioxidant and antiproliferative activities of common fruits
J. Agric. Food Chem.
Antioxidant and antiproliferative activities of vegetables
J. Agric. Food Chem.
Cited by (153)
Phenolic extract of Morchella angusticeps peck inhibited the proliferation of HepG2 cells in vitro by inducing the signal transduction pathway of p38/MAPK
2020, Journal of Integrative AgricultureCordia dichotoma: A Comprehensive Review of its Phytoconstituents and Endophytic Fungal Metabolites and their Potential Anticancer Effects
2024, Current Topics in Medicinal Chemistry