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Hormones and Cancer

, Volume 5, Issue 5, pp 312–323 | Cite as

The Lack of Antitumor Effects of o,p′DDA Excludes Its Role as an Active Metabolite of Mitotane for Adrenocortical Carcinoma Treatment

  • Ségolène Hescot
  • Angelo Paci
  • Atmane Seck
  • Abdelhamid Slama
  • Say Viengchareun
  • Séverine Trabado
  • Sylvie Brailly-Tabard
  • Abir Al Ghuzlan
  • Jacques Young
  • Eric Baudin
  • Marc LombèsEmail author
Original Paper

Abstract

Mitotane (o,p′DDD) is the most effective treatment of advanced adrenocortical carcinoma (ACC) but its mechanism of action remains unknown. Previous studies suggested that o,p′DDA may represent the active metabolite of mitotane. We aimed at reevaluating the potential role and pharmacological effects of o,p′DDA. Functional consequences of o,p′DDA exposure were studied on proliferation, steroidogenesis, and mitochondrial respiratory chain in human H295R and SW13 adrenocortical cells. Mitotane and its metabolites were quantified using high-performance liquid chromatography combined to an ultraviolet detection in these cells treated with o,p′DDD or o,p′DDA and in human adrenal tissues. Dose–response curves up to 300 μM showed that, as opposed to o,p′DDD, o,p′DDA did not inhibit cell proliferation nor alter respiratory chain complex IV activity, gene expression nor induce mitochondrial biogenesis, oxidative stress, or apoptosis. However, whereas mitotane drastically decreased expression of genes involved in steroidogenesis, o,p′DDA slightly reduced expression of some steroidogenic enzymes and exerts weak anti-secretory effects only at high doses. While o,p′DDD concentration was significantly reduced by 40 % in H295R cell supernatants after 48 h incubation, o,p′DDA levels remained unchanged suggesting that o,p′DDA was not efficiently transported into the cells. o,p′DDA was not detected in cell homogenates or supernatants after 48 h exposure to o,p′DDD, consistent with the absence of o,p′DDA production in these models. Finally, unlike op′DDD, we found that o,p′DDA content was undetectable in two ACC and one normal adrenal gland of mitotane-treated patients, suggesting a lack of cellular uptake and in situ production. Our results demonstrate that o,p′DDD, but not o,p′DDA, induces functional alterations in adrenal cells.

Keywords

SW13 Cell Mitochondrial Biogenesis Adrenal Cell Mitotane Adrenocortical Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors are indebted to HRA Pharma for supporting this research. This work was supported by the Institut National de la Santé et de la Recherche Médicale (Inserm) and Université Paris-Sud. SH is recipient of a fellowship from HRA Pharma Laboratories (Bourse CIFRE).

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12672_2014_189_MOESM1_ESM.docx (12 kb)
Supplemental Table 1 (DOCX 12 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Ségolène Hescot
    • 1
    • 2
    • 3
  • Angelo Paci
    • 4
  • Atmane Seck
    • 4
  • Abdelhamid Slama
    • 5
  • Say Viengchareun
    • 1
    • 2
  • Séverine Trabado
    • 1
    • 2
    • 6
  • Sylvie Brailly-Tabard
    • 1
    • 2
    • 6
  • Abir Al Ghuzlan
    • 7
  • Jacques Young
    • 1
    • 2
    • 8
  • Eric Baudin
    • 1
    • 2
    • 3
  • Marc Lombès
    • 1
    • 2
    • 8
    Email author
  1. 1.Inserm U693Le Kremlin-Bicêtre CedexFrance
  2. 2.Faculté de Médecine Paris-Sud, UMR-S693Univ Paris-SudLe Kremlin-BicêtreFrance
  3. 3.Department of Nuclear Medicine and Endocrine TumorsGustave Roussy Cancer Campus Grand ParisVillejuifFrance
  4. 4.Pharmacology and Drug Analysis DepartmentGustave Roussy Cancer Campus Grand ParisVillejuifFrance
  5. 5.Assistance Publique-Hôpitaux de Paris, Service de Biochimie, CHU BicêtreLe Kremlin BicêtreFrance
  6. 6.Assistance Publique-Hôpitaux de Paris, Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, CHU BicêtreLe Kremlin BicêtreFrance
  7. 7.Department Medical Biology and PathologyGustave Roussy Cancer Campus Grand ParisVillejuifFrance
  8. 8.Assistance Publique-Hôpitaux de Paris, Service d’Endocrinologie et des Maladies de la Reproduction, CHU BicêtreLe Kremlin BicêtreFrance

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