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In vitro antitumor activity of progesterone in human adrenocortical carcinoma

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Abstract

Purpose

The management of patients with adrenocortical carcinoma (ACC) is challenging. As mitotane and chemotherapy show limited efficacy, there is an urgent need to develop therapeutic approaches. The aim of this study was to investigate the antitumor activity of progesterone and explore the molecular mechanisms underlying its cytotoxic effects in the NCI-H295R cell line and primary cell cultures derived from ACC patients.

Methods

Cell viability, cell cycle, and apoptosis were analyzed in untreated and progesterone-treated ACC cells. The ability of progesterone to affect the Wnt/β-catenin pathway in NCI-H295R cells was investigated by immunofluorescence. Progesterone and mitotane combination experiments were also performed to evaluate their interaction on NCI-H295R cell viability.

Results

We demonstrated that progesterone exerted a concentration-dependent inhibition of ACC cell viability. Apoptosis was the main mechanism, as demonstrated by a significant increase of apoptosis and cleaved-Caspase-3 levels. Reduction of β-catenin nuclear translocation may contribute to the progesterone cytotoxic effect. The progesterone antineoplastic activity was synergically increased when mitotane was added to the cell culture medium.

Conclusions

Our results show that progesterone has antineoplastic activity in ACC cells. The synergistic cytotoxic activity of progesterone with mitotane provides the rationale for testing this combination in a clinical study.

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Abbreviations

ACC:

adrenocortical carcinoma

PgR:

progesterone receptor

IC:

Interval of Confidence

MTT:

3-(4,5-Dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide

mPR:

progesterone membrane receptor

PGRMC1:

progesterone receptor membrane component 1

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Funding

This work was supported by: AIRC project IG17678 (PI: M.T.); AIRC project IG14411 (PI: A.B.); Fondazione Camillo Golgi, Brescia; University of Brescia local grants; private donation of “gli Amici di Andrea” in memory of Andrea Gadeschi; private grant from the amateur dramatics group “Attori non per caso”, Parish church of Collio Valtrompia (Brescia). M.F. was supported by a grant from the Italian Society of Pharmacology.

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Authors and Affiliations

  1. Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

    Martina Fragni, Chiara Fiorentini, Elisa Rossini, Sara Vezzoli, Sara A. Bonini, Cristina Missale, Maurizio Memo & Sandra Sigala

  2. Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia and ASST Spedali Civili di Brescia, Brescia, Italy

    Simona Fisogni & Fabio Facchetti

  3. Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia and ASST Spedali Civili di Brescia, Brescia, Italy

    Cristina Dalmiglio, Salvatore Grisanti, Melanie Claps, Deborah Cosentini & Alfredo Berruti

  4. Surgical Clinic, Department of Clinical and Experimental Sciences, University of Brescia and ASST Spedali Civili di Brescia, Brescia, Italy

    Guido A. M. Tiberio

  5. Section of Oncology and Experimental Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

    Valentina Salvi & Daniela Bosisio

  6. Department of Clinical and Biological Sciences University of Turin, Internal Medicine 1, San Luigi Gonzaga Hospital, Orbassano, Italy

    Massimo Terzolo

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  1. Martina Fragni
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  2. Chiara Fiorentini
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Correspondence to Alfredo Berruti.

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Fragni, M., Fiorentini, C., Rossini, E. et al. In vitro antitumor activity of progesterone in human adrenocortical carcinoma. Endocrine 63, 592–601 (2019). https://doi.org/10.1007/s12020-018-1795-x

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