J Agric Food Chem. 2008 Dec 24;56(24):11661-7.
Apple phytochemical extracts inhibit proliferation of estrogen-dependent and estrogen-independent human breast cancer cells through cell cycle modulation.
Sun J,
Liu RH.
Department of Food Science, Cornell University, Ithaca, New York 14853, USA.
Breast cancer is the most commonly diagnosed cancer in women in the United States. Dietary modification, particularly increased intake of fruits and vegetables, has been consistently associated with a reduced risk of various cancers, including breast cancer. Apples are a major source of dietary phytochemicals and flavonoids and possess potent antioxidant activity and antiproliferative activity in vitro. However, the molecular mechanisms of the anticancer properties of apple phytochemical extracts are not completely understood. In this study a possible mechanism by which apple extracts could inhibit cancer cell growth in vitro using estrogen-dependent MCF-7 and estrogen-independent MDA-MB-231 human breast cancer cell lines was analyzed. The data showed that apple phytochemical extracts significantly inhibited human breast cancer MCF-7 and MDA-MB-231 cell proliferation at concentrations of 10-80 mg/mL (p < 0.05). DNA flow cytometric analysis showed that apple extracts significantly induced G1 arrest in MCF-7 cells in a dose-dependent manner at concentrations >20 mg/mL (p < 0.05). At concentrations of 15, 30, and 50 mg/mL, apple extracts caused a greater increase in the G1/S ratio in MDA-MB-231 cells when compared with MCF-7 cells (p < 0.05). Cyclin D1 and Cdk4 proteins, the two major G1/S transit regulators, decreased in a dose-dependent manner after exposure to apple extracts. These results suggest that the antiproliferative activities of apple phytochemical extracts toward human breast cancer cells might be due to the modulation effects on cell cycle machinery.
PMID: 19053381 [PubMed - indexed for MEDLINE]
J Agric Food Chem. 2009 Jan 14;57(1):297-304.
Fresh apples suppress mammary carcinogenesis and proliferative activity and induce apoptosis in mammary tumors of the Sprague-Dawley rat.
Liu JR,
Dong HW,
Chen BQ,
Zhao P,
Liu RH.
Department of Food Science and Institute of Comparative and Environmental Toxicology, Cornell University, Ithaca, New York 14853-7201, USA.
Whole apple extracts possess potent antioxidant activity and antiproliferative activity against cancer cells in vitro. The objectives of this study were to determine the anticancer activity of apple extracts in a rat mammary cancer model induced by 7,12-dimethylbenz(a)anthracene (DMBA) in vivo and to determine if apple extracts inhibited cell proliferation and affected apoptosis in mammary cancer tissues in vivo. Rats were given the whole apple extracts (0, 3.3, 10.0, or 20.0 g/kg of body weight) by gavage starting 2 weeks prior to DMBA administration and continuing for 24 weeks. Rats treated with DMBA (positive control) developed mammary tumors with 71.4% tumor incidence during the 24-week study. No tumors were detected in the negative control group untreated with DMBA. A dose-dependent inhibition of mammary carcinogenesis by apple extracts was observed (P < 0.01). Tumor multiplicity decreased with increasing apple extracts. Histopathological evaluations of tumors were performed. The proportions of adenocarcinoma masses decreased with increasing apple extracts. The expression of proliferating cell nuclear antigen (PCNA), cyclin D1, and Bcl-2 decreased, and Bax expression and apoptosis increased with increasing apple extracts. These results demonstrate the potent capacity of fresh apples to suppress DMBA-initiated mammary cancers in rats.
PMID: 19072049 [PubMed - indexed for MEDLINE]
Mol Carcinog. 2009 May;48(5):420-31.
Apple polyphenol phloretin potentiates the anticancer actions of paclitaxel through induction of apoptosis in human hep G2 cells.
Yang KC,
Tsai CY,
Wang YJ,
Wei PL,
Lee CH,
Chen JH,
Wu CH,
Ho YS.
Division of Gastroenterology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, School of Medicine, Taipei Medical University, Taipei, Taiwan.
Phloretin (Ph), which can be obtained from apples, apple juice, and cider, is a known inhibitor of the type II glucose transporter (GLUT2). In this study, real-time PCR analysis of laser-capture microdissected (LCM) human hepatoma cells showed elevated expression (>5-fold) of GLUT2 mRNA in comparison with nonmalignant hepatocytes. In vitro and in vivo studies were performed to assess Ph antitumor activity when combined with paclitaxel (PTX) for treatment of human liver cancer cells. Inhibition of GLUT2 by Ph potentiated the anticancer effects of PTX, resensitizing human liver cancer cells to drugs. These results demonstrate that 50-150 microM Ph significantly potentiates DNA laddering induced in Hep G2 cells by 10 nM PTX. Activity assays showed that caspases 3, 8, and 9 are involved in this apoptosis. The antitumor therapeutic efficacy of Ph (10 mg/kg body weight) was determined in cells of the SCID mouse model that were treated in parallel with PTX (1 mg/kg body weight). The Hep G2-xenografted tumor volume was reduced more than fivefold in the Ph + PTX-treated mice compared to the PTX-treated group. These results suggest that Ph may be useful for cancer chemotherapy and chemoprevention.
PMID: 18767070 [PubMed - indexed for MEDLINE]
Int J Cancer. 2009 May 1;124(9):2210-9.
In vitro and in vivo study of phloretin-induced apoptosis in human liver cancer cells involving inhibition of type II glucose transporter.
Wu CH,
Ho YS,
Tsai CY,
Wang YJ,
Tseng H,
Wei PL,
Lee CH,
Liu RS,
Lin SY.
Graduate Institute of Clinical Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
Phloretin (Ph), a natural product found in apples and pears with glucose transporter (GLUT) inhibitory activity, exerts antitumor effects. However, little is known about its effects on human liver cancer. The purpose of this study is to test the cytotoxic effects of Ph on HepG2 cells and to identify the underlying molecular pathways. Human hepatocellular carcinoma specimens and HepG2 show a high level of GLUT2 transporter activity in the cell membrane. Real-time PCR and MTT assays demonstrate that Ph-induced cytotoxicity correlates with the expression of GLUT2. Flow cytometry and DNA fragmentation studies show that 200 microM Ph induces apoptosis in HepG2, which was reversed by glucose pretreatment. GLUT2 siRNA knockdown induced HepG2 apoptosis, which was not reversed by glucose. Western blot analysis demonstrates that both intrinsic and extrinsic apoptotic pathways in addition to Akt and Bcl-2 family signaling pathways are involved in Ph-induced cell death in HepG2 cells. Furthermore, using flow cytometry analysis, a mitochondrial membrane potential assay and Western blot analysis, we show that cytochalasin B, a glucose transport inhibitor, enhances the Ph-induced apoptotic effect on HepG2 cells, which was reversed by pretreatment with glucose. Furthermore, we found significant antitumor effects in vivo by administering Ph at 10 mg/kg intraperitoneally to severe combined immune deficiency mice carrying a HepG2 xenograft. A microPET study in the HepG2 tumor-bearing mice showed a 10-fold decrease in (18)F-FDG uptake in Ph-treated tumors compared to controls. Taken together, these results suggest that Ph-induced apoptosis in HepG2 cells involves inhibition of GLUT2 glucose transport mechanisms. (c) 2008 Wiley-Liss, Inc.
PMID: 19123483 [PubMed - indexed for MEDLINE]
Nutr Cancer. 2009;61(4):510-7.
In vitro measures used to predict anticancer activity of apple cultivars and their comparison to outcomes from a rat model of experimentally induced breast cancer.
Thompson MD,
Stushnoff C,
McGinley JN,
Thompson HJ.
Colorado State University, Fort Collins, Colorado, USA.
Experiments reported herein tested the hypothesis that cultivars of apple (Malus domestica Borkh.) would demonstrate anticancer activity in vivo as predicted by in vitro measures. Freeze dried powders of Red Delicious (RD), Fuji (FJ), Golden Delicious (GD), and Granny Smith (GS) apple cultivars were evaluated. Significant differences were noted among cultivars in total phenolics (P < 0.0001), flavonoids (P < 0.0003), oxygen radical absorbance capacity (P < 0.0001), and growth inhibition in the MDA-MB-468 human breast cancer cell line relative to vehicle-treated cells (P < 0.0001). These findings were extended to predict inhibition of the postinitiation phase of 1-methyl-1-nitrosourea-induced mammary carcinogenesis by freeze-dried whole apple powders of the same cultivars. Although rats fed apple-containing diets did not have lower incidence or multiplicity of cancers than rats fed control diet, a finding consistent with epidemiological reports on fruit and breast cancer risk, differences among cultivars were noted, with the greatest difference in cancer multiplicity between GS and RD (1.46 vs. 2.47 cancers/rat; P = 0.0159). The rate of cell proliferation in mammary carcinomas differed between GS and RD (P < 0.001), whereas the apoptotic rate did not. These findings suggest altered methodology for screening apples for anticancer activity and that more diverse apple cultivars with higher phytochemical content should be evaluated.
PMID: 19838923 [PubMed - indexed for MEDLINE]
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