Retinoic Acid Prevents Cushing Syndrome in Mouse Model

[Guest NewsItem]

from http://diabetes.medscape.com/44967.rhtml?s...-111601

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ALIGN="center"><B>Retinoic Acid Prevents Cushing Syndrome in Mouse Model</B></P>

WESTPORT, CT (Reuters Health) Nov 09 - Retinoic acid inhibits the production of ACTH adrenocorticotropic hormone (ACTH) and corticosterone by experimental ACTH-secreting tumors in nude mice, according to a report in the October issue of the Journal of Clinical Investigation.

"We first thought of testing retinoic acid after we observed in detail the molecular mechanisms that control the biosynthesis of ACTH in the pituitary," Dr. Marcelo Paez-Pereda from Max Planck Institute of Psychiatry in Munich, Germany told Reuters Health. "The production of this enzyme is under the transcriptional control of AP-1 and Nur77, and these transcription factors were found to be inhibited by retinoic acid in other cells."

Dr. Paez-Pereda and colleagues tested the effects of retinoic acid on neuroendocrine tumor cell lines and in experimental ACTH-secreting tumors implanted in nude mice.

Retinoic acid inhibited the AP-1-directed and Nur77/Nurr1-directed transcription of pro-opiomelanocortin promoter and the consequent production of ACTH in ACTH-secreting cells, the authors report.

In primary culture, 24 hours of treatment with 10 nanomolar retinoic acid inhibited ACTH production in six out of eight ACTH-secreting Cushing tumors, the report indicates. Retinoic acid also inhibited ACTH production by NCI-N592, a small-cell lung cancer cell line.

In contrast, retinoic acid did not influence the production of ACTH, prolactin, or growth hormone by normal rat pituitary cells, the researchers note, and did not alter the basal corticosterone production in adrenal cortex cells in culture. Retinoic acid did, however, inhibit forskolin-stimulated corticosterone secretion and cell proliferation in adrenal cortex cells.

In cell proliferation assays, retinoic acid induced apoptosis and inhibited anchorage-independent colony formation, the results indicate.

Pretreatment of ACTH-secreting cells with retinoic acid substantially reduced their ability to form tumors after injection into nude mice, the report indicates, with only 20% of mice developing small tumors after 5 weeks.

When injected after the development of ACTH-secreting tumors in nude mice, the investigators say, retinoic acid completely blocked tumor growth.

"All these results indicate that retinoic acid might be an interesting therapeutic option to inhibit ACTH, cortisol, and tumor growth in Cushing syndrome," the authors conclude.

"At the moment, there is no efficient drug treatment for Cushing syndrome, and the surgical removal of the tumor has side effects and is not always effective," Dr. Paez-Pereda said. "Therefore, we believe that retinoic acid is a promising drug to be tested in clinical trials in Cushing syndrome."

"We are planning to conduct a multicenter phase II clinical trial of retinoic acid in patients with Cushing syndrome caused by pituitary tumors," Dr. Paez-Pereda added.

J Clin Invest 2001;108:1123-1131.

[Shauna]

Wow..that's really interesting.

Why do the poor mice have to be nude? (LOL)

[Guest Lynne Clemens]

Ha! Shauna, that's what I wanted to know.

[Guest Kristin]

Has anyone heard anything more about the proposed clinical trial? Or about cushing's and retinoic acid?

 

Retinoic acid is related to Vitamin A and also to Accutane/RetinA the acne treatments. And has been used for years to treat a form of leukemia. So the nice thing about this would be extensive experience on dose and side effects in humans already -- not starting from mice.

 

It seems like this would be an ideal way to reduce cortisol in those who have ACTH overproduction from whatever reason.

 

I think I better eat more carrots!

 

Kristin