Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Mar;43(3):357-367.
doi: 10.1007/s40618-019-01127-1. Epub 2019 Oct 5.

The effects of mitotane and 1α,25-dihydroxyvitamin D3 on Wnt/beta-catenin signaling in human adrenocortical carcinoma cells

B Rubin  1 , C Pilon  1 , R Pezzani  2 , A Rebellato  1 , F Fallo  3
Affiliations

The effects of mitotane and 1α,25-dihydroxyvitamin D3 on Wnt/beta-catenin signaling in human adrenocortical carcinoma cells

B Rubin et al. J Endocrinol Invest. 2020 Mar.

Abstract

Purpose: Mitotane is the only chemotherapeutic agent available for the treatment of adrenocortical carcinoma (ACC), however, the anti-neoplastic efficacy is limited due to several side-effects in vivo. There is, therefore, a need of exploring for new anti-tumoral agents which can be used either alone or in combination with mitotane. The active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) acts as an anti-proliferative agent in human cancer by inhibiting the Wnt/beta-catenin pathway through the vitamin D receptor (VDR). The aim of this study was to study the effects of mitotane and 1α,25(OH)2D3, individually or in combination, in an in vitro model with H295R ACC cells, and to elucidate the molecular events behind their effects involving the Wnt/beta-catenin signaling.

Methods and results: Multiple concentrations of mitotane and 1α,25(OH)2D3, individually or in combination, were tested on H295R cells for 24-96 h, and the effects analysed by MTT. A reduction in cell growth was observed in a dose/time-dependent manner for both mitotane and 1α,25(OH)2D3. In addition, a combination of clinically sub-therapeutic concentrations of mitotane with 1α,25(OH)2D3, had an additive anti-proliferative effect (Combination Index = 1.02). In a wound healing assay, individual treatments of both mitotane and 1α,25(OH)2D3 reduced the migration ability of H295R cells, with the effect further enhanced on combining both the agents. Western blotting and qRT-PCR analysis showed a modulation of the Wnt/beta-catenin and VDR signaling pathways.

Conclusion: Our results show an additive effect of mitotane and 1α,25(OH)2D3 on the inhibition of H295R ACC cell growth and viability, and suggest that molecular mechanisms of their effects involve a functional link between VDR and Wnt/beta-catenin pathways.

Keywords: 1α,25-Dihydroxyvitamin D3; Adrenocortical cancer cells; Mitotane; Wnt/beta-catenin.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, Jolly S, Miller BS, Giordano TJ, Hammer GD (2014) Adrenocortical carcinoma. Endocr Rev 35(2):282–326 - PubMed
    1. Stigliano A, Chiodini I, Giordano R, Faggiano A, Canu L, Della Casa S, Loli P, Luconi M, Mantero F, Terzolo M (2016) Management of adrenocortical carcinoma: a consensus statement of the Italian Society of Endocrinology (SIE). J Endocrinol Investig 39(1):103–121
    1. Paragliola RM, Torino F, Papi G, Locantore P, Pontecorvi A, Corsello SM (2018) Role of mitotane in adrenocortical carcinoma—review and state of the art. Eur Endocrinol 14(2):62–66 - PubMed - PMC
    1. Fassnacht M, Dekkers OM, Else T, Baudin E, Berruti A, de Krijger R, Haak HR, Mihai R, Assie G, Terzolo M (2018) European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 179(4):G1–G46 - PubMed
    1. Waszut U, Szyszka P, Dworakowska D (2017) Understanding mitotane mode of action. J Physiol Pharmacol 68(1):13–26 - PubMed

MeSH terms

Grants and funding

LinkOut - more resources