title: Morphofunctional effects of mitotane on mitochondria in human adrenocortical cancer cells.
abstract: At present, mitotane (MTT) represents the first-line pharmacological approach for the treatment of advanced adrenocortical carcinoma (ACC). Despite clear evidence that the drug can reduce the clinical signs of steroid excess in secreting ACC, the mechanism mediating the possible toxic effect of MTT on tumor cells still remains obscure. This study investigated the intracellular events underlying the toxic effect of MTT by studying qualitative and quantitative alterations in mitochondrial morphology and functions in human adrenocortical cancer cell lines, H295R and SW13. Increasing concentrations of MTT resulted in rapid intracellular accumulation and conversion of the drug. Cytostatic and cytotoxic effects were evident at doses corresponding to the therapeutic window (30-50 μM) through an apoptotic mechanism involving caspase 3/7. Electron microscopic analysis of cell mitochondria displayed MTT-induced dose- and time-dependent alterations in the morphology of the organelle. These alterations were characterized by a marked swelling and a decrease in the number of respiratory cristae, accompanied by a significant depolarization of the mitochondrial membrane potential, finally leading to the disruption of the organelle. A drastic reduction of oxygen consumption was observed due to mitochondrial membrane damage, which was accompanied by a decrease in the levels of VDAC1 integral membrane channel. These findings contribute to better understand the intracellular mechanism of action of MTT in ACC cells, showing that its cytotoxic effect seems to be mainly mediated by an apoptotic process activated by the disruption of mitochondria.
authors.affiliation: Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, Research Unit of Histology and Embryology, University of Florence, Viale Pieraccini 6, Florence, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Poli
authors.forename: Daniele
authors.initials: D
authors.lastname: Guasti
authors.forename: Elena
authors.initials: E
authors.lastname: Rapizzi
authors.forename: Rossella
authors.initials: R
authors.lastname: Fucci
authors.forename: Letizia
authors.initials: L
authors.lastname: Canu
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bandini
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Cini
authors.forename: Daniele
authors.initials: D
authors.lastname: Bani
authors.forename: Massimo
authors.initials: M
authors.lastname: Mannelli
authors.forename: Michaela
authors.initials: M
authors.lastname: Luconi
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000378:metabolism*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003633:Dichlorodiphenyl Dichloroethylene / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D008939:Mitotane / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D003633:Dichlorodiphenyl Dichloroethylene; D008939:Mitotane; D010100:Oxygen
keywords: adrenal cortex; carcinoma; intracellular signalling