, Volume 63, Issue 3, pp 592–601 | Cite as

In vitro antitumor activity of progesterone in human adrenocortical carcinoma

  • Martina Fragni
  • Chiara Fiorentini
  • Elisa Rossini
  • Simona Fisogni
  • Sara Vezzoli
  • Sara A. Bonini
  • Cristina Dalmiglio
  • Salvatore Grisanti
  • Guido A. M. Tiberio
  • Melanie Claps
  • Deborah Cosentini
  • Valentina Salvi
  • Daniela Bosisio
  • Massimo Terzolo
  • Cristina Missale
  • Fabio Facchetti
  • Maurizio Memo
  • Alfredo BerrutiEmail author
  • Sandra Sigala
Original Article



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.


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.


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.


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.


Adrenocortical carcinoma Progesterone Progesterone receptor Cell viability 



adrenocortical carcinoma


progesterone receptor


Interval of Confidence


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


progesterone membrane receptor


progesterone receptor membrane component 1



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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

12020_2018_1795_MOESM1_ESM.docx (791 kb)
Supplementary data


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Martina Fragni
    • 1
  • Chiara Fiorentini
    • 1
  • Elisa Rossini
    • 1
  • Simona Fisogni
    • 2
  • Sara Vezzoli
    • 1
  • Sara A. Bonini
    • 1
  • Cristina Dalmiglio
    • 3
  • Salvatore Grisanti
    • 3
  • Guido A. M. Tiberio
    • 4
  • Melanie Claps
    • 3
  • Deborah Cosentini
    • 3
  • Valentina Salvi
    • 5
  • Daniela Bosisio
    • 5
  • Massimo Terzolo
    • 6
  • Cristina Missale
    • 1
  • Fabio Facchetti
    • 2
  • Maurizio Memo
    • 1
  • Alfredo Berruti
    • 3
    Email author
  • Sandra Sigala
    • 1
  1. 1.Section of Pharmacology, Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
  2. 2.Pathology Unit, Department of Molecular and Translational MedicineUniversity of Brescia and ASST Spedali Civili di BresciaBresciaItaly
  3. 3.Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public HealthUniversity of Brescia and ASST Spedali Civili di BresciaBresciaItaly
  4. 4.Surgical Clinic, Department of Clinical and Experimental SciencesUniversity of Brescia and ASST Spedali Civili di BresciaBresciaItaly
  5. 5.Section of Oncology and Experimental Immunology, Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
  6. 6.Department of Clinical and Biological Sciences University of Turin, Internal Medicine 1San Luigi Gonzaga HospitalOrbassanoItaly

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