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. 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.

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