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The Lack of Antitumor Effects of o,p′DDA Excludes Its Role as an Active Metabolite of Mitotane for Adrenocortical Carcinoma Treatment
- Source :
- Hormones and Cancer. 5:312-323
- Publication Year :
- 2014
- Publisher :
- Springer Science and Business Media LLC, 2014.
-
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.
- Subjects :
- Cancer Research
medicine.medical_specialty
Endocrinology, Diabetes and Metabolism
Apoptosis
Biology
Article
Electron Transport Complex IV
03 medical and health sciences
0302 clinical medicine
Endocrinology
Cell Line, Tumor
Internal medicine
Adrenocortical Carcinoma
medicine
Humans
Adrenocortical carcinoma
Mitotane
Cell Proliferation
030304 developmental biology
0303 health sciences
Endocrine and Autonomic Systems
Adrenal gland
Cell growth
Mitochondrial Turnover
medicine.disease
Adrenal Cortex Neoplasms
3. Good health
Enzyme Activation
Oxidative Stress
medicine.anatomical_structure
Mitochondrial respiratory chain
Oncology
Mechanism of action
Mitochondrial biogenesis
030220 oncology & carcinogenesis
Adrenal Cortex
Steroids
medicine.symptom
medicine.drug
Subjects
Details
- ISSN :
- 18688500 and 18688497
- Volume :
- 5
- Database :
- OpenAIRE
- Journal :
- Hormones and Cancer
- Accession number :
- edsair.doi.dedup.....6420dfcc429e8c822ee0e9dab17cc764