Growth suppression of mouse pituitary corticotroph tumor AtT20 cells by curcumin: a model for treating Cushing's disease.
BACKGROUND
Pituitary corticotroph tumors secrete excess adrenocorticotrophic hormone (ACTH) resulting in Cushing's disease (CD). Standard treatment includes surgery and, if not successful, radiotherapy, both of which have undesirable side effects and frequent recurrence of the tumor. Pharmacotherapy using PPARgamma agonists, dopamine receptor agonists, retinoic acid or somatostatin analogs is still experimental. Curcumin, a commonly used food additive in South Asian cooking, has potent growth inhibitory effects on cell proliferation. Our laboratory recently demonstrated that curcumin inhibited growth and induced apoptosis in prolactin- and growth hormone-producing tumor cells. Subsequently, Schaaf et.al. confirmed our findings and also showed the in vivo effectiveness of curcumin to suppress pituitary tumorigenesis. However the molecular mechanism that mediate this effect of curcumin are still unknown.


RESULTS
Using the mouse corticotroph tumor cells, AtT20 cells, we report that curcumin had a robust, irreversible inhibitory effect on cell proliferation and clonogenic property. The curcumin-induced growth inhibition was accompanied by decreased NFkappaB activity. Further, curcumin down-regulated the pro-survival protein Bcl-xL, depolarized the mitochondrial membrane, increased PARP cleavage, which led to apoptotic cell death. Finally, curcumin had a concentration-dependent suppressive effect on ACTH secretion from AtT20 cells.


CONCLUSIONS
The ability of curcumin to inhibit NFkappaB and induce apoptosis in pituitary corticotroph tumor cells leads us to propose developing it as a novel therapeutic agent for the treatment of CD.
Bangaru
Madhavi Latha Yadav
ML
DepDepartment of Endocrinology, Metabolism & Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Woodliff
Jeffrey
J
Raff
Hershel
H
Kansra
Sanjay
S
D049913:ACTH-Secreting Pituitary Adenoma / Q000188:drug therapy* / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003474:Curcumin / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D047748:Pituitary ACTH Hypersecretion / Q000188:drug therapy*
D000970:Antineoplastic Agents; D016328:NF-kappa B; D000324:Adrenocorticotropic Hormone; D003474:Curcumin
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