Abstract B101: Breast cancer chemoprevention by a novel oleanane triterpenoid: Preclinical evidence

Abstract

Abstract Breast cancer is the most frequently diagnosed cancer in women in both developed and developing countries. Breast cancer remains highly resistant to chemotherapy and thus a major preventive approach, such as chemoprevention, is considered an important and viable strategy in reversing the morbidity and mortality of this disease. Several plant triterpenoids, including oleananes, have exhibited significant promise as chemopreventive agents against breast cancer. Amooranin (AMR), a triterpene acid (25-hydroxy-3-oxoolean-12-en-28-oic acid) isolated from Amoora rohituka (an Indian medicinal plant), has been shown to inhibit mammary tumorigenesis both in vitro and in vivo. Methyl-25-hydroxy-3-oxoolean-12-en-28-oate (AMR-Me) is a novel synthetic AMR analog with superior antitumor effects to AMR against a panel of human breast carcinoma cells. Nevertheless, mechanism-based chemopreventive potential of AMR-Me has not been tested in an experimentally validated preclinical model of breast cancer. The objective of the present study was to investigate the chemopreventive potential and underlying mechanisms of action of AMR-Me against 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary carcinogenesis, an experimental rodent tumor model that closely resembles human mammary cancer. Rats were treated with three doses of AMR-Me (0.8, 1.2 and 1.6 mg/kg body weight) three times per week by oral gavage. Following two weeks of this treatment protocol, mammary tumorigenesis was initiated by DMBA (50 mg/kg body weight, per os). The treatment of rats with AMR-Me was continued. All animals were sacrificed 16 weeks following the DMBA exposure and the incidence and burden of mammary tumors were estimated. AMR-Me (at 1.2 or 1.6 mg/kg) displayed a striking attenuation of DMBA-induced mammary tumor incidence, total tumor burden, average tumor weight, and intratumor histopathological alterations without toxic effects. AMR-Me inhibited abnormal cell proliferation and induced apoptosis in mammary tumors. AMR-Me also upregulated the transcriptional levels of Bax, Bad, caspase-3, caspase-7 and poly (ADP-ribose) polymerase and downregulated Bcl-2. Based upon these results, we conclude that oral AMR-Me exerts a significant chemopreventive effect in DMBA-induced mammary tumorigenesis in rats through suppression of abnormal cell proliferation as well as induction of apoptosis in a dose-responsive fashion. The apoptosis-inducing effect of AMR-Me during mammary carcinogenesis may be mediated through promotion of mitochondrial pro-apoptotic mechanism. AMR-Me has considerable potential as a safe chemopreventive drug for human breast cancer that represents a dismal disease. This study was supported by a grant (R03CA136014) from the National Cancer Institute (NCI)/National Institutes of Health (NIH). The content of this abstract is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. Citation Format: Anupam Bishayee, Roslin J. Thoppil, Animesh Mandal, Altaf S. Darvesh, Deepak Bhatia. Breast cancer chemoprevention by a novel oleanane triterpenoid: Preclinical evidence. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B101.