Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor use in the management of resistant hypercholesterolemia induced by mitotane treatment for adrenocortical cancer

Tsakiridou, Efthymia D.; Liberopoulos, Evangelos; Giotaki, Zoe; Tigas, Stelios

doi:10.1016/j.jacl.2018.03.078

Cited by 5 publications

(5 citation statements)

References 9 publications

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“…DHEA, dehydroepiandrosterone. statin therapy (59). Thus, we suggest that the model we here established might help to develop strategies to overcome mitotane resistance in vitro, which could then be further investigated in clinical trials.…”

Section: Figurementioning

confidence: 83%

Generation and characterization of a mitotane-resistant adrenocortical cell line

Seidel

Walenda

Messerschmidt

et al. 2020

Endocrine Connections

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Mitotane is the only drug approved for the therapy of adrenocortical carcinoma (ACC). Its clinical use is limited by the occurrence of relapse during therapy. To investigate the underlying mechanisms in vitro, we here generated mitotane-resistant cell lines. After long-term pulsed treatment of HAC-15 human adrenocortical carcinoma cells with 70 µM mitotane, we isolated monoclonal cell populations of treated cells and controls and assessed their respective mitotane sensitivities by MTT assay. We performed exome sequencing and electron microscopy, conducted gene expression microarray analysis and determined intracellular lipid concentrations in the presence and absence of mitotane. Clonal cell lines established after pulsed treatment were resistant to mitotane (IC50 of 102.2 ± 7.3 µM (n = 12) vs 39.4 ± 6.2 µM (n = 6) in controls (biological replicates, mean ± s.d., P = 0.0001)). Unlike nonresistant clones, resistant clones maintained normal mitochondrial and nucleolar morphology during mitotane treatment. Resistant clones largely shared structural and single nucleotide variants, suggesting a common cell of origin. Resistance depended, in part, on extracellular lipoproteins and was associated with alterations in intracellular lipid homeostasis, including levels of free cholesterol, as well as decreased steroid production. By gene expression analysis, resistant cells showed profound alterations in pathways including steroid metabolism and transport, apoptosis, cell growth and Wnt signaling. These studies establish an in vitro model of mitotane resistance in ACC and point to underlying molecular mechanisms. They may enable future studies to overcome resistance in vitro and improve ACC treatment in vivo.

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Section: Figurementioning

confidence: 83%

Generation and characterization of a mitotane-resistant adrenocortical cell line

Seidel

Walenda

Messerschmidt

et al. 2020

Endocrine Connections

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“…Importantly, this dose decreased intratumor cholesterol content, supporting our hypothesis that a reduction in intratumor cholesterol can decrease ACC growth. Interest for statins is not new for the therapy of ACC, however, it has been considered in association with mitotane to reduce hypercholesterolemia (6,33). Our data instead suggest the possibility of using lipophilic statins without mitotane but eventually with cytotoxic drugs.…”

Section: Discussionmentioning

confidence: 77%

Statins Reduce Intratumor Cholesterol Affecting Adrenocortical Cancer Growth

Trotta

Avena

Chimento

et al. 2020

Molecular Cancer Therapeutics

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Mitotane causes hypercholesterolemia in ACC patients. We suppose that cholesterol increases within the tumor and can be used to activate proliferative pathways. In this study, we used statins to decrease intratumor cholesterol and investigated the effects on ACC growth related to ERα action at the nuclear and mitochondrial levels. We first used microarray to investigate mitotane effect on genes involved in cholesterol homeostasis and evaluated their relationship with patients' survival in ACC TCGA.We then blocked cholesterol synthesis with simvastatin and determined the effects on H295R cell proliferation, estradiol production and ERα activity in vitro and in xenograft tumors. We found that mitotane increases intratumor cholesterol content and expression of genes involved in cholesterol homeostasis, among them INSIG, whose expression affects patients' survival. Treatment of H295R cells with simvastatin to block cholesterol synthesis decreased cellular cholesterol content and this affected cell viability. Simvastatin reduced estradiol production and decreased nuclear and mitochondrial ERα function. A mitochondrial target of ERα, the respiratory complex IV (COX IV) was reduced after simvastatin treatment, which profoundly affected mitochondrial respiration activating apoptosis. In vivo experiments confirmed the ability of simvastatin to reduce tumor volume and weight of grafted H295R cells, intratumor cholesterol content, Ki-67 and ERα, COX IV expression and activity and increase TUNEL positive cells. Collectively these data demonstrate that a reduction in intratumor cholesterol content prevents estradiol production, inhibits mitochondrial respiratory chain inducing apoptosis in ACC cells. Inhibition of mitochondrial respiration by simvastatin represents a novel strategy to counteract ACC growth.

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“…This effect is of particular importance as it could potentially self-promote drug resistance [ 1 , 26 ]. On this basis, several in vitro and clinical studies were recently conducted to evaluate how to counteract resistance to mitotane by lowering lipoprotein levels through, for example, statins or PCSK9 inhibitors [ 61 , 62 , 68 ]. In a recent clinical case, the strategy of targeting the PCSK9 gene [ 68 ], which encodes an enzyme expressed mainly in the liver and intestine with an important role in lipid metabolism, was reported.…”

Section: Culture Conditions and Mitotane Cytotoxicity: A Need For Reappraisalmentioning

confidence: 99%

“…On this basis, several in vitro and clinical studies were recently conducted to evaluate how to counteract resistance to mitotane by lowering lipoprotein levels through, for example, statins or PCSK9 inhibitors [ 61 , 62 , 68 ]. In a recent clinical case, the strategy of targeting the PCSK9 gene [ 68 ], which encodes an enzyme expressed mainly in the liver and intestine with an important role in lipid metabolism, was reported. PCSK9 binds to the LDL receptor favoring its degradation with the effect of increasing circulating LDL.…”

Section: Culture Conditions and Mitotane Cytotoxicity: A Need For Reappraisalmentioning

confidence: 99%

“…This effect allowed to increase the dose of mitotane and to reach therapeutic plasma levels. These data indicate that treatment with PCSK9 inhibitors should be considered in patients who develop mitotane-related hypercholesterolemia that cannot be managed with conventional lipid-lowering treatment [ 68 ].…”

Section: Culture Conditions and Mitotane Cytotoxicity: A Need For Reappraisalmentioning

confidence: 99%

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

Iacono

Puglisi

Perotti

et al. 2021

Cancers

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Mitotane is the only approved drug for the treatment of advanced adrenocortical carcinoma and is increasingly used for postoperative adjuvant therapy. Mitotane action involves the deregulation of cytochromes P450 enzymes, depolarization of mitochondrial membranes, and accumulation of free cholesterol, leading to cell death. Although it is known that mitotane destroys the adrenal cortex and impairs steroidogenesis, its exact mechanism of action is still unclear. The most used cell models are H295-derived cell strains and SW13 cell lines. The diverging results obtained in presumably identical cell lines highlight the need for a stable in vitro model and/or a standard methodology to perform experiments on H295 strains. The presence of several enzymatic targets responsive to mitotane in mitochondria and mitochondria-associated membranes causes progressive alteration in mitochondrial structure when cells were exposed to mitotane. Confounding factors of culture affecting in vitro experiments could reduce the significance of any molecular mechanism identified in vitro. To ensure experimental reproducibility, particular care should be taken in the choice of culture conditions: aspects such as cell strains, culture serum, lipoproteins concentration, and culture passages should be carefully considered and explicated in the presentation of results. We aimed to review in vitro studies on mitotane effects, highlighting how different experimental conditions might contribute to the controversial findings. If the concerns pointed out in this review will be overcome, the new insights into mitotane mechanism of action observed in-vitro could allow the identification of novel pharmacological molecular pathways to be used to implement personalized therapy.

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Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor use in the management of resistant hypercholesterolemia induced by mitotane treatment for adrenocortical cancer

Cited by 5 publications

References 9 publications

Generation and characterization of a mitotane-resistant adrenocortical cell line

Generation and characterization of a mitotane-resistant adrenocortical cell line

Statins Reduce Intratumor Cholesterol Affecting Adrenocortical Cancer Growth

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

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