Inhibitors+of+27HC

Matthew Perez and Erik Christensen

ICI 182,780: What is ICI 182,780?

ICI 182,780 (also known as Fulvestrant when in drug form) is an estrogen receptor (ER) antagonist that is used to limit estrogen receptor activity. It is used mainly in post menopausal women who have a recurrence of ER positive breast cancer or who have had a metastasis of ER positive breast cancer. Due to its antagonist behavior, it is very effective in preventing the binding of estrogen and preventing any further growth of an ER positive tumor (//Fulvestrant Injection)//. How does ICI 182,780 relate to 27HC?

With its ER antagonist nature, ICI 182,780 is very effective to use against 27HC as well. It really works no differently than it does with estrogen, and arguably works better because 27HC does not have as high of an affinity for the ER as estrogen does, making it easier for ICI 182,780 to compete for binding “rights.” When it was tested in mice, it was found to be very effective. Figure 1A illustrates how ICI 182,780 was the most effective treatment for 27HC other than discontinuing the administering of 27HC to the mice (Nelson). This is very promising. However, there is even more promising information. When ICI 182,780 was paired with CYP7B1, it caused for the inhibiti on of tumor growth, eventually causing about 30% of the tumors to stay below 500mm³(Figure 1D). The ability for this inhibitor/ enzyme pair to stop the growth of a tumor is very significant and is a great avenue of treatment. Finally, in Figure 1F, we see that 27HC paired with ICI 182,780 works to inhibit tumor volume. Effectiveness is determined by the fact that ICI 182,780 treatment allowed less tumor growth than the placebo treatment. ICI 182,780 is a very good inhibitor of 27HC and seems like it would be a great treatment for ER positive breast cancer and 27HC promotion of the cancer (Nelson).

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GW3965 induces LXR:
= = =What is GW3965 and LXR? =

GW3965 is a liver x-receptor (LXR) agonist. That is it promotes the function of LXR, which is very important in cholesterol synthesis(//GW3965 Hydrochloride)//. The function of the LXR in the liver is to control cholesterol metabolism. They work to sense the levels of cholesterol in the body and work accordingly to help either raise or lower the levels of cholesterol based on the body’s need. As shown in Figure 2, when LXR is activated it works to excrete cholesterol, lowering the levels in the cells and throughout the body(Zhao). It works through many pathways to induce increased efflux of cholesterol, along with its metabolites (Zhao). GW3965 works to keep LXR functioning without signals from the body. This works to limit the amount of cholesterol and its metabolites in the body, helping to lower the induction of breast cancer tumor growth among other cholesterol related diseases. How well does the GW3965/LXR tandem work on breast cancer?

When LXR action is promoted by GW3965, it has very impressive effects on breast cancer. When tested in mice, researchers found that it was a very good inhibitor of tumor growth, limiting the growth to less than the growth seen with the placebo. That is the amount of tumors in mice growing more than 500mm³ takes much longer when in the presence of the GW3965, which inhibits their LXR (Figure 1E)(Nelson). Also, in conjunction with that, we see that the time it takes for tumor mass to increase takes much longer than the placebo when the mouse is given GW3965 (Figure 1F)(Nelson). By limiting cholesterol metabolites, 27HC is in lower abundance and therefore you see less cell proliferation of the ER positive breast cancer. This would defiantly explain the decrease in the amount of tumor growth experienced by the mice. Works Cited: Links to sources please
 * 1) Nelson, E. R., S. E. Wardell, J. S. Jasper, S. Park, S. Suchindran, M. K. Howe, N. J. Carver, R. V. Pillai, P. M. Sullivan, V. Sondhi, M. Umetani, J. Geradts, and D. P. Mcdonnell. "27-Hydroxycholesterol Links Hypercholesterolemia and Breast Cancer Pathophysiology." // Science // 342.6162 (2013): 1094-098. Web.
 * 2) "Fulvestrant Injection: MedlinePlus Drug Information." // U.S National Library of Medicine //. U.S. National Library of Medicine, n.d. Web. 02 June 2014.
 * 3) "GW3965 Hydrochloride." // ≥98% (HPLC), Powder //<span style="background-color: rgba(255,255,255,0.0980392); line-height: 1.5;">. N.p., n.d. Web. 02 June 2014.
 * 4) <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Zhao, C., and K. Dahlman-Wright. "Liver X Receptor in Cholesterol Metabolism." // Journal of Endocrinology // 204.3 (2010): 233-40. Web.

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