Abstract 4563: Muscadine grape extract reduces lung carcinogenesis in female mice exposed to 3-methylcholanthrene in utero

Abstract

Abstract The developing fetus is highly sensitive to the carcinogenic effects of dietary and environmental carcinogens in cigarette smoke, charbroiled foods and air pollution following transplacental exposure. Oxidative metabolism of toxicants by both maternal and fetal tissue causes DNA damage which can ultimately result in the initiation of childhood cancers. Due to the latency of cancer formation, in utero exposure to carcinogens may even predispose the individual to cancers developing later in life. The goal of this study is to determine whether a proprietary muscadine grape extract (MGE) effectively reduces lung tumor formation in the fetus following transplacental exposure to a polycyclic hydrocarbon. The muscadine grape (Vitis rotundifolia) has a distinct phytochemical composition compared to other grape varieties and limited reports indicate that the extract has potential anti-tumor activity. BALB/c male mice were mated to C57BL/6 female mice to serve as a model for in utero exposure to environmental toxicants. The pregnant mice were treated on the 17th day of gestation by intraperitoneal injection with a 45 mg/kg dose of 3-methylcholanthrene dissolved in olive oil, to induce lung tumors in the fetus. An injection of the olive oil vehicle (0.5 mL/0.35 kg) served as the control. Day 0 was considered as the first day when the vaginal plug was detected. After weaning, cohorts of mice received drinking water alone or water with MGE (approximately 1.0 mg phenolics/25 g mouse) and were sacrificed at 12 months of age. Although all of the mice developed lung tumors, MGE significantly reduced tumor burden in female mice by approximately 48% as compared to the tumor tissue found in control mice drinking regular water (12.4 ± 1.9 g versus 6.5 ± 1.2 g, n = 26-32, p = 0.014). In addition, tumor multiplicity was higher in control mice as compared to MGE-treated animals (6.8 ± 0.4 observed tumors versus 4.2 ± 0.5 observed tumors, n = 26-32, p = 0.0001). Tumor tissue sections from mice administered MGE had a significant decrease in proliferating cell nuclear antigen as compared to tumors from control animals (22.4 ± 1.8 versus 14.2 ± 1.3, p = 0.0009), suggesting that in part MGE reduces tumor burden by decreasing tumor cell proliferation. Lung tumor sections from female mice drinking regular water or MGE were incubated with an antibody to the endothelial cell marker, CD34, and vessels were identified by a combination of morphology and positive CD34 immunoreactivity. MGE significantly reduced blood vessel density in lung tumor tissue as compared to female mice drinking regular water (20.5 ± 2.2 versus 11.3 ± 1.3, p = 0.0012), suggesting that the grape extract inhibits angiogenesis. These results indicate that MGE reduces both tumor proliferation and angiogenesis, leading to a decrease in tumor burden and multiplicity. Thus, MGE may represent a novel nutraceutical for the prevention of lung tumors induced by in utero exposure to environmental toxicants. Citation Format: Brooke E. Porter, Joseph E. Moore, Mark S. Miller, E. Ann Tallant, Patricia E. Gallagher. Muscadine grape extract reduces lung carcinogenesis in female mice exposed to 3-methylcholanthrene in utero. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4563. doi:10.1158/1538-7445.AM2015-4563