title: The lack of antitumor effects of o,p'DDA excludes its role as an active metabolite of mitotane for adrenocortical carcinoma treatment.
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 o'p'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.
authors.affiliation: Inserm U693, Fac Med Paris Sud, 63 rue Gabriel Péri, 94276, Le Kremlin-Bicêtre Cedex, France.
authors.forename: Ségolène
authors.initials: S
authors.lastname: Hescot
authors.forename: Angelo
authors.initials: A
authors.lastname: Paci
authors.forename: Atmane
authors.initials: A
authors.lastname: Seck
authors.forename: Abdelhamid
authors.initials: A
authors.lastname: Slama
authors.forename: Say
authors.initials: S
authors.lastname: Viengchareun
authors.forename: Séverine
authors.initials: S
authors.lastname: Trabado
authors.forename: Sylvie
authors.initials: S
authors.lastname: Brailly-Tabard
authors.forename: Abir
authors.initials: A
authors.lastname: Al Ghuzlan
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
authors.forename: Eric
authors.initials: E
authors.lastname: Baudin
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000306:Adrenal Cortex Neoplasms / Q000378:metabolism*; D018268:Adrenocortical Carcinoma / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D063269:Mitochondrial Turnover / Q000187:drug effects; D008939:Mitotane / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D013256:Steroids / Q000096:biosynthesis
chemical_list: D013256:Steroids; C054917:2,2-(2-chlorophenyl-4'-chlorophenyl)acetic acid; D008939:Mitotane; D003576:Electron Transport Complex IV