Largazole as a Novel and Selective Anti-Breast Cancer Agent. Addendum
Final rept. 17 Sep 2012-16 Sep 2013, addendum
YALE UNIV NEW HAVEN CT
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The goal of this study was is to explore the biological activity of largazole, a cyclic depsipeptide natural product with remarkable potency in selectively inhibiting the proliferation of breast cancer cells without significant effects on normal breast mammary epithelial cells. Specifically, we set out to test the idea that dual-specificity of small molecules capable of targeting two or more aberrant signaling pathways associated with human cancers will be more efficacious in suppressing human tumors. This hypothesis was based on our initial observation that largazole and analogs inhibit both histone deacetylases and also the human ubiquitin E1 enzyme. Included in the scope of the research was the synthesis of additional quantities of largazole, studies to determine whether dual inhibition of both HDAC and ubiquitin conjugation is responsible for the selectivity of largazole against breast cancer cells and determine which HDAC isoforms render breast epithelial cells sensitive to largazole, and initial efforts to determine the chemotherapeutic efficacy of largazole to inhibit breast cancer growth and metastasis in mice.
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