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Interesting Clinical Study Item

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J Clin Invest, October 2001, Volume 108, Number 8, 1123-1131

Copyright ?2001 by the American Society for Clinical Investigation


Retinoic acid prevents experimental Cushing syndrome

Marcelo P?ez-Pereda1, Damian Kovalovsky2, Ursula Hopfner1, Marily Theodoropoulou1, Uberto Pagotto1, Eberhard Uhl3, Marco Losa4, Johanna Stalla1, Yvonne Gr?bler1, Cristina Missale5, Eduardo Arzt2 and G?nter K. Stalla1


1 Max Planck Institute of Psychiatry, Munich, Germany

2 Laboratorio de Fisiolog?a y Biolog?a Molecular, Universidad de Buenos Aires and Argentine National Research Council (CONICET), Ciudad Universitaria, Buenos Aires, Argentina

3 Department of Neurosurgery, University of Munich, Munich, Germany

4 Department of Neurosurgery, San Raffaele Scientific Research Institute (IRCCS) San Raffaele, University of Milano, Milano, Italy

5 Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy


Address correspondence to: Marcelo P?ez-Pereda, Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany. Phone: 49-89-30622-272; Fax: 49-89-30622-605; E-mail: marcelo{at}mpipsykl.mpg.de.


Received for publication August 17, 2000, and accepted in revised form August 27, 2001.


ABTRACT: Cushing syndrome is caused by an excess of adrenocorticotropic hormone (ACTH) production by neuroendocrine tumors, which subsequently results in chronic glucocorticoid excess. We found that retinoic acid inhibits the transcriptional activity of AP-1 and the orphan receptors Nur77 and Nurr1 in ACTH-secreting tumor cells. Retinoic acid treatment resulted in reduced pro-opiomelanocortin transcription and ACTH production. ACTH inhibition was also observed in human pituitary ACTH-secreting tumor cells and a small-cell lung cancer cell line, but not in normal cells. This correlated with the expression of the orphan receptor COUP-TFI, which was found in normal corticotrophs but not in pituitary Cushing tumors. COUP-TFI expression in ACTH-secreting tumor cells blocked retinoic acid action. Retinoic acid also inhibited cell proliferation and, after prolonged treatment, increased caspase-3 activity and induced cell death in ACTH-secreting cells. In adrenal cortex cells, retinoic acid inhibited corticosterone production and cell proliferation. The antiproliferative action and the inhibition of ACTH and corticosterone produced by retinoic acid were confirmed in vivo in experimental ACTH-secreting tumors in nude mice. Thus, we conclude that the effects of retinoic acid combine in vivo to reverse the endocrine alterations and symptoms observed in experimental Cushing syndrome.


Full study report is at above provided link.....



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