The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 13 No.
2 • April 2010
Emerging Medicine: Angiogenesis Inhibitor
What Does Athlete’s Foot Have to Do with Angiogenesis?
Answer: You’d be surprised. A new paper reports that a common and readily available prescription drug for athlete’s foot, itraconazole, inhibits both mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2) in endothelial cells, suppressing growth and proliferation and, hence, angiogenesis. The closely related drug micronazole is available without a prescription as Micatin™ or Monistat.™ However, we don’t know whether micronazole would work as an angiogenesis inhibitor.
In the introduction to their paper, the authors explain that “[a]mong the upstream signals that are known to affect the mTOR pathway are growth factors, nutrients such as amino acids, cellular energy status, and a variety of environmental stresses.” They note that cholesterol is an important cellular building block. The researchers had screened a library of known drugs in an earlier study looking for inhibitors of angiogenesis and found that one of the most potent hits was an antifungal drug itraconazole. In their followup studies on itraconazole, they have found a link between intracellular cholesterol trafficking and the mTOR pathway in endothelial cells. “Here we report that itraconazole causes blockade of cholesterol egress from endosomal/lysosomal compartments to the plasma membrane, which, in turn, leads to inhibition of both mTORC1 and mTORC2. We provide multiple lines of evidence that mTOR activity in endothelial cells requires proper cholesterol trafficking, adding plasma membrane cholesterol to the list of signal inputs to regulate the mTOR pathway.”
As they explain, “... in the absence of proper cholesterol distribution to the plasma membrane (and likely other intracellular membranes), the mTOR pathway is turned off, leading to the inhibition of endothelial cell [HUVECs, human umbilical vein endothelial cells] proliferation.” This inhibition suggests that the drug may be useful in inhibiting angiogenesis, which requires endothelial cell proliferation. The researchers state that the mTOR inhibitor rapamycin and its analogue temsirolimus both inhibit tumor angiogenesis in vivo and directly inhibit endothelial cell proliferation in vitro. Both mTORC1 and mTORC2 are required for endothelial cell proliferation. Skin cancer might be a potential target for therapy with itraconazole, but we don’t know whether effects might differ between the various types of skin cancer, such as basal cell, squamous cell, and melanoma.
The authors also examined the sensitivity of other cell types to the inhibition of the mTOR pathway induced by itraconazole in endothelial cells and found that endothelial cells are, indeed, particularly sensitive to this effect. HeLa cells, for example, were found to be significantly less sensitive to itraconazole than HUVECS.
Note that itraconazole has many drug interactions when taken orally.
- Xu et al. Cholesterol trafficking is required for mTOR activation in endothelial cells. Proc Natl Acad Sci U S A 107(10):4764-9 (2010).
That rifle on the wall of the labourer’s cottage or working class flat is the symbol of democracy. It is our job to see that it stays there.
— George Orwell
(D&S: Sorry, George. The UK blew it.)
. . . don’t plan your research to fit the supposed dictates of funding agencies—I’ve never done the experiments proposed in any of my grant applications.
— Solomon H. Snyder
(D&S: Hmmm. This practice worked out well for outstanding scientists like Dr. Snyder, but it would appear to make the funding somewhat lacking in accountability if everybody can lie about what they plan to do with the money.)