Molecular Mechanisms of Mitotane Action in Adrenocortical Cancer Based on In Vitro Studies

Iacono, Marco Lo; Puglisi, Soraya; Perotti, Paola; Saba, L.; Petiti, Jessica; Giachino, Claudia; Reimondo, Giuseppe; Terzolo, Massimo

doi:10.3390/cancers13215255

Cited by 17 publications

(14 citation statements)

References 66 publications

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“…Mitotane is the only adrenolytic drug approved for ACC adjuvant treatment. It exerts its adrenolytic action through the alterations in the function of mitochondria and by blocking adrenal steroid 11-β-hydroxylation [ 3 ]. In this study, we investigated the possible influence of mitotane plasma concentration on dyslipidemia in patients with complete tumor resection, separately evaluating man, females, and premenopausal and postmenopausal women.…”

Section: Discussionmentioning

confidence: 99%

“…In the mitochondria of adrenal cells, mitotane is metabolized in o,p’-DDE (1,1-(o,p’-Dichlorodiphenyl)-2,2 dichloroethene) through α-hydroxylation and o,p’-DDA (1,1-(o,p’-Dichlorodiphenyl) acetic acid) through β-hydroxylation [ 2 ]. Although it is known that mitotane causes the apoptosis of adrenal cells through the deregulation of cytochromes P450 enzymes, the depolarization of mitochondrial membranes and the accumulation of free cholesterol, its exact mechanism of action is still inadequately elucidated at the molecular level due to conflicting findings from in vitro studies [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

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Sex-Based Evaluation of Lipid Profile in Postoperative Adjuvant Mitotane Treatment for Adrenocortical Carcinoma

et al. 2022

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Background: A wide interindividual variability in mitotane concentrations and treatment-related dyslipidemia have been reported. Here, we aimed to underline the sex-related differences in the lipid profile in patients that underwent radical surgery of adrenocortical carcinoma during treatment with adjuvant mitotane. Methods: A chromatographic method was used to quantify the drug in plasma collected from adult patients with complete tumor resection, also considering active metabolite o,p’-DDE. Results: We observed different lipid profiles between males and females and between pre- and post-menopausal women. Considering the mitotane-related effects on lipid levels, we observed that higher drug concentrations were correlated with higher HDL in all the considered groups (p < 0.001), with total cholesterol both in males (p = 0.005) and females (p = 0.036), with triglycerides in postmenopausal females (p = 0.002) and with LDL in male patients (p < 0.001). Increases in o,p’-DDE were positively correlated with HDL levels in all the groups (p < 0.001) and negatively with LDL in all the groups (males p = 0.008, pre- and post-menopausal females p < 0.001), with total cholesterol in pre- (p = 0.016) and post-menopausal women (p = 0.01) and with triglycerides in premenopausal females (p = 0.005). Conclusions: This is the first study designed to evaluate sex differences in lipoprotein and lipid levels during mitotane adjuvant treatment; the results suggest that a gender and personalized approach could be useful to prevent and manage alterations in the lipid profile.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sex-Based Evaluation of Lipid Profile in Postoperative Adjuvant Mitotane Treatment for Adrenocortical Carcinoma

et al. 2022

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“…Mitotane action involves the deregulation of cytochromes P450 enzymes, depolarization of mitochondrial membranes, and accumulation of free cholesterol, leading to cell death. However, its exact mechanism of action remains poorly defined at a molecular level due to controversial results generated by in vitro studies (53).…”

Section: Surgerymentioning

confidence: 99%

ENDOCRINE TUMOURS: Our experience with the management of patients with non-metastatic adrenocortical carcinoma

Terzolo

Fassnacht

2022

European Journal of Endocrinology

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Adrenocortical carcinoma (ACC) accounts for a minority of all malignant tumors in adults. Surgery remains the most important therapeutic option for non-metastatic ACC. Whether a subset of patients with small ACC may benefit from minimally invasive surgery remains a debated issue, but we believe that surgeon’s expertise is more important than surgical technique to determine outcome. However, even a state-of-the-art surgery cannot prevent disease recurrence that is determined mainly by specific tumor characteristics. We consider that the concomitant presence of the following features characterizes a cohort of patients at low risk of recurrence, i) R0 resection (microscopically free margin), ii) localized disease (stage I-II ACC), and iii) low grade tumor (ki-67 <10%). After the ADIUVO study, we do not recommend adjuvant mitotane as a routine measure for such patients, who can be managed with active surveillance thus sparing a toxic treatment. Patients at average risk of recurrence should be treated with adjuvant mitotane. For patients at very high risk of recurrence, defined as the presence of at least one of the following: Ki67 >30%, large venous tumor thrombus, R1 resection or stage IV ACC, we increasingly recommend to combine mitotane with four cycles of platinum-based chemotherapy. However, patients at moderate-to-high risk of recurrence should be ideally enrolled in the ongoing ADIUVO2 trial. We do not use frequently adjuvant radiotherapy of the tumor bed at our institutions, and we select for this treatment patients with microscopically, or macroscopically, incomplete resection. On long-term, prospective multicenter trials are required to improve patient care.

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“…Radical surgical resection of ACC is the most effective therapeutic strategy for localized tumours, but the risk of recurrence remains high 12 . In patients with advanced inoperable or metastatic ACC, the adrenolytic compound mitotane, a derivate of the insecticide DDT, remains the standard of care, used as a single agent or in combination with an etoposide-doxorubicinplatin polychemotherapy [13][14][15] . Although these treatments can improve recurrence free survival, their benefit on overall survival is still debated 12,13,[16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

Sexually dimorphic activation of innate antitumour immunity prevents adrenocortical carcinoma development

Wilmouth

Olabe

Garcia-Garcia

et al. 2022

Preprint

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SummaryIn contrast with most cancers, adrenocortical carcinomas (ACC) are more frequent in women than men, but the underlying mechanisms of this sexual dimorphism remain elusive. Homozygous deletion of the negative WNT pathway regulator ZNRF3 is the most frequent alteration in ACC patients. Here, we show that Cre-mediated inactivation of Znrf3 in steroidogenic cells of the mouse adrenal cortex is associated with sexually dimorphic tumour progression. Indeed, although most knockout female mice develop metastatic carcinomas over an 18 month-time course, adrenal hyperplasia gradually regresses in male knockout mice. This male-specific regression is associated with induction of senescence and recruitment of macrophages, which differentiate as active phagocytes that clear-out senescent preneoplastic cells. Macrophage recruitment is also observed in female mice. However, it is delayed and dampened compared to males, which allows for tumour progression. Interestingly, testosterone treatment of female knockouts is sufficient to induce senescence, recruitment of phagocytic macrophages and regression of hyperplasia. We further show that although macrophages are present within adrenal tumours at 18 months, MERTKhigh active phagocytes are mostly found in indolent lesions in males but not in aggressive tumours in females. Consistent with our observations in mice, analysis of RNA sequencing data from the TCGA cohort of ACC shows that phagocytic macrophages are more prominent in men than women and associated with better prognosis. Altogether, these data establish that phagocytic macrophages prevent aggressive ACC development in male mice and suggest that they may play a key role in the unusual sexual dimorphism of ACC in patients.

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Molecular Mechanisms of Mitotane Action in Adrenocortical Cancer Based on In Vitro Studies

Cited by 17 publications

References 66 publications

Sex-Based Evaluation of Lipid Profile in Postoperative Adjuvant Mitotane Treatment for Adrenocortical Carcinoma

Sex-Based Evaluation of Lipid Profile in Postoperative Adjuvant Mitotane Treatment for Adrenocortical Carcinoma

ENDOCRINE TUMOURS: Our experience with the management of patients with non-metastatic adrenocortical carcinoma

Sexually dimorphic activation of innate antitumour immunity prevents adrenocortical carcinoma development

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