Growth suppression of mouse pituitary corticotroph tumor AtT20 cells by curcumin: a model for treating Cushing's disease.

Madhavi Latha Yadav Bangaru,Sanjay Kansra,Jeffrey Woodliff,Hershel Raff

doi:10.1371/journal.pone.0009893

Madhavi Latha Yadav Bangaru, Sanjay Kansra + Show 2 more

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https://doi.org/10.1371/journal.pone.0009893

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Abstract

BackgroundPituitary 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 PPARγ 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 [1]. 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.Principal FindingsUsing 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 NFκB 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.ConclusionThe ability of curcumin to inhibit NFκB and induce apoptosis in pituitary corticotroph tumor cells leads us to propose developing it as a novel therapeutic agent for the treatment of CD.

Highlights

Pituitary tumors, not generally metastatic in nature, do result in morbidity due to both altered hormonal patterns as well as side effects of therapy [2]
The ability of curcumin to inhibit NFkB and induce apoptosis in pituitary corticotroph tumor cells leads us to propose developing it as a novel therapeutic agent for the treatment of Cushing’s disease (CD)
AtT20 cells were treated with curcumin (2.5– 200 mM) and cell proliferation was assessed after 4 days

Summary

Introduction

Not generally metastatic in nature, do result in morbidity due to both altered hormonal patterns as well as side effects of therapy [2]. Pituitary corticotroph tumors secrete excess ACTH resulting in CD. To date no standard reliable medical therapy exists to decrease ACTH secretion in CD. Medical therapies are still experimental with approaches to suppressing ACTH secretion including, D2R agonists, somatostatin receptor antagonist, thiazolidinediones (PPARc agonists) and retinoic acid [4,5,6,7]. 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. The molecular mechanism that mediate this effect of curcumin are still unknown

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