Diindolymethane - Natural Protection from Estrogens

Estrogen plays a role in ovarian tumorigenesis. Aromatase is the enzyme required for the synthesis of estrogen via conversion of androgen to estrogen, which is the major source of estrogen in postmenopausal women. Aromatase is present in normal ovaries and other tissues (e.g., fat and muscle) as well as in 33-81% tumor tissues of ovarian cancer. Aromatase inhibitors (AIs) block estrogen synthesis by inhibiting aromatase activity. In patients with recurrent ovarian cancer, single-agent AI therapy has been shown to elicit clinical response rates of up to 35.7% and stable disease rates of 20-42%. Given the limited treatment options for recurrent ovarian cancer and the favorable safety profile and convenient use, AI is a rational option for prolonging platinum-free interval in recurrent ovarian cancer. Further studies are required to determine the efficacy of combination treatment with AIs and biological agents, determine the benefit of AIs for treating special types of ovarian cancer (e.g., endometrioid type), and identify biomarkers for targeted patient selection. This review summarizes the current epidemiologic, preclinical, and clinical data regarding estrogen's role in ovarian cancer, the expression and regulation of aromatase in this disease, the development and characteristics of the three generations of AIs, and the preclinical and clinical studies of AIs in the treatment of ovarian cancer.

Several compounds that selectively inhibit estrogen synthesis via aromatase have been developed

Aromatase is a membrane-bound hemeprotein of the endoplasmic reticulum. It is the only known enzyme to catalyze the biosynthesis of estrogens from androgens. Crystallization of aromatase (CYP19A1), arguably the most unique cytochrome P450 in vertebrates, and a major breast cancer drug target, remained elusive for decades. Our unusual approach of crystallizing the human placental enzyme, as in the case of steroid sulfatase, has finally been vindicated by the growth of the first crystal of the full-length microsomal P450. The structure provides an unprecedented glimpse into the active site of a substrate-specific estrogen-synthesizing catalytic machine, unlike those of the drug- and xenobiotic-metabolizing P450s or numerous published homology models, and has opened a floodgate of opportunities for the rational design of next generation aromatase inhibitors.


7 Foods that Inhibit Aromatase Enzyme Naturally | Anabolic …

Currently, structure-based design, synthesis and evaluation of the next generation aromatase inhibitors constitute a major objective of the aromatase project. Several compounds synthesized by structure-guided design have shown great promise in our laboratory evaluation. We have conducted anti-proliferative assays on these promising candidates in a MCF-7 breast cancer cell line. Some show inhibitory and anti-proliferative properties better than those of the well-known breast cancer drug exemestane. For decades many laboratories have made attempts to crystallize various recombinant forms of human aromatase by deleting the N-terminal trans-membrane domain, but no crystal was reported. Using a bacterial construct of the amino terminus truncated aromatase we have now been able to address this problem. We have crystallized the recombinant aromatase and determined the crystal structure. In addition, some of the mutagenesis studies that we have already conducted raise interesting possibilities with regard to its oligomerization and functional issues. By incorporating the recombinant aromatase into our research plan, we have taken the aromatase and novel inhibitor discovery research to the next level. We have also initiated an investigation into the effects of environmental chemicals and endocrine-disrupting agents such as fungicides on aromatase and estrogen biosynthesis, and their mechanisms of action. Additionally, collaborative efforts are underway to extend our structure-function research into elucidating the possible roles of aromatase in the CNS and neuroendocrine effects of estrogen, as well as into rational design of antibodies as diagnostic tools for the detection of a super-active form of aromatase in estrogen-dependent breast tumors.