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DEGUELIN AS A THERAPEUTIC DRUG FOR TRIPLE NEGATIVE AND METASTATIC BREAST CANCER
Title
DEGUELIN AS A THERAPEUTIC DRUG FOR TRIPLE NEGATIVE AND METASTATIC BREAST CANCER
Creator
Kalra, Amit
Date
2011-12-13, 2011-12
Description
Breast cancer is a second leading cause of cancer related deaths. 15-20 % of women with Breast cancer are diagnosed with Triple negative...
Show moreBreast cancer is a second leading cause of cancer related deaths. 15-20 % of women with Breast cancer are diagnosed with Triple negative breast cancer (ER, PR, and HER2 –ve) which is the most aggressive type showing higher incidence of recurrence at the local as well as distant sites. Conventional chemotherapy, which shows high levels of toxicity, is the only option available for triple negative breast cancer as hormonal therapy does not work. Thus new drugs which could successfully inhibit the growth of triple negative breast cancer along with the inhibition of metastasis are highly desired. Deguelin, originally isolated from an African plant Mundulea sericea is shown to be effective in skin, lung, breast and colon cancer, effect is thought to be mediated by downregulation of the PI3K/AKT pathway. However, its effect on triple negative breast cancer in vitro and in vivo has not been evaluated. There are few in vivo experimental models to study the effect of novel drugs for the therapy of TNBCs. Murine 4T1 mammary breast cancer cell model is so far the most appropriate experimental model to study efficacy of new drugs on not only tumor growth but also on metastasis to different visceral organs including lungs. This model is relevant and mimics stage IV breast cancer in women. We evaluated the effects of Deguelin on triple negative and highly metastatic breast cancer cell line MDA MB 231 and also In vivo in the 4T1 breast cancer model. We also evaluated effect of Deguelin in combination with low dose (IC30) Taxol. Deguelin treatment alone inhibited the growth of MDA MB 231 breast cancer cells in a time and dose dependent manner causing S-G2 arrest. Deguelin induced apoptosis and inhibited cell proliferation. Deguelin also induced changes in the cell shape and subcellular distribution of the cytoskeletal (F-actin and Tubulin) and cell-cell attachment protein beta-catenin. Growth inhibitory effect was enhanced when Deguelin was given along with low dose Taxol. In vivo, Deguelin (2 or 6mg/kg body weight) administered daily for 21 days significantly (P<0.05) inhibited growth of 4T1 cells transplanted s.c. in to 4-6 weeks old female BALB/c mice. Interestingly, as compared to vehicle only, Deguelin treatment also significantly (P<0.02) reduced the number of metastatic lesions from intravenously injected 4T1 cells. Western blot analysis of several key signaling proteins in MDA MB 231 cells suggested that Deguelin (250nM) reduces PI3K, pAKT, and NF-κB protein levels. Immunohistochemical studies in 4T1 xenografts and metastatic lung lesions obtained from vehicle and Deguelin treated animals suggested that Deguelin reduces pAKT, COX2 and HIF-1 alpha, major key players involved in angiogenesis, cell proliferation and metastasis. In conclusion, our results show that Deguelin has growth inhibitory effect on TNBC cell lines; it inhibits in vivo and in vitro growth of murine mammary cancer cell line. Deguelin has anti metastatic activity in 4T1 experimental model. Anti proliferative and anti metastatic effects of Deguelin are mediated through down regulation of pAKT, COX2 and HIF-1 alpha. Deguelin alone or in combination to Taxol showed promising results and could be further developed as potential drugs for the treatment of triple negative breast cancer.
M.S. in Biology, December 2011
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