Abstract 3829: Inhibition of breast cancer metastasis by deguelin in an experimental model

Abstract

Breast cancer is a second leading cause of cancer related deaths in women. Cancer related deaths in breast cancer patients are due to metastasis of disease. Thus new drugs which could successfully inhibit metastatic disease spread are highly desired. However till date there are only a few experimental models available to study metastatic progression of breast cancer. Murine 4T1 mammary breast cancer cells when transplanted s.c./or into mammary gland metastasizes to lungs, liver and bone similar to that observed in women with stage IV metastatic disease. Thus this model is highly appropriate for studies related to breast cancer metastasis. Previously we have shown that Deguelin, originally isolated from an African plant Mundulea sericea significantly inhibits the growth of triple negative breast cancer and that the Deguelin effect is mediated through inhibition of WNT signaling pathway. However their therapeutic effect in vivo is still unexplored. We evaluated the effects of Deguelin on growth (in vitro and in vivo) and lung metastasis of 4T1 cells. In vitro, Deguelin inhibited growth of 4T1 cells in time and concentration depended manner; optimum growth inhibition was obtained at 250nM Deguelin concentration after 72 hr. treatment. Toxicity study performed in 4-6 weeks old female BALB/c mice suggested that Deguelin administered as a suspension (saline/gum Arabic/Deguelin) daily for two weeks by intraperitoneal (i.p.) injection was well tolerated up to 16mg/kg body weight, and no toxicity (loss of appetite, body weight loss, mobility, morbidity, death) was observed in Deguelin treated animals. In vivo, as compared to vehicle treated animals, Deguelin (2 or 6mg/kg body weight) administered daily for 21 days i.p significantly (P<0.05) inhibited growth of 4T1 cells (0.5 million cells/mouse) transplanted s.c. in to 4-6 weeks old female BALB/c mice. Similarly Deguelin also reduced (27-33%, P< 0.02) the number of metastatic lesions in the lungs subsequent to i.v. injection of 7500 to 10,000 4T1 cells in syngeneic mice as compared to vehicle treated control group. Immunohistochemical analysis of control/Deguelin treated 4T1 cells, and lung metastatic lesions suggest that Deguelin inhibited Ki67 expression suggesting its antiproliferative action in this model. In addition, phospho AKT, cyclin D1, Cox-2 and Hif-1α protein expressions were down regulated. Our results suggest that Deguelin effect on the growth and metastasis may be mediated by targeting signaling molecules involved in pAKT, HIF-1, Cox-2 pathway. These results provide a promising lead for a potential therapeutic agent to treat metastatic breast cancer. This work was supported in part by the National Cancer Institute grant CA140321. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3829. doi:1538-7445.AM2012-3829