Molecular Mechanisms of Mitotane Action in Adrenocortical Cancer Based on In Vitro Studies
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 cholestero...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/21/5255 |
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| author | Marco Lo Iacono Soraya Puglisi Paola Perotti Laura Saba Jessica Petiti Claudia Giachino Giuseppe Reimondo Massimo Terzolo |
| author_facet | Marco Lo Iacono Soraya Puglisi Paola Perotti Laura Saba Jessica Petiti Claudia Giachino Giuseppe Reimondo Massimo Terzolo |
| author_sort | Marco Lo Iacono |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T04:37:39Z |
| format | Article |
| id | doaj.art-0fa15dcc1fd64291ae06db3812e4c83f |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T04:37:39Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-0fa15dcc1fd64291ae06db3812e4c83f2023-12-03T13:24:42ZengMDPI AGCancers2072-66942021-10-011321525510.3390/cancers13215255Molecular Mechanisms of Mitotane Action in Adrenocortical Cancer Based on In Vitro StudiesMarco Lo Iacono0Soraya Puglisi1Paola Perotti2Laura Saba3Jessica Petiti4Claudia Giachino5Giuseppe Reimondo6Massimo Terzolo7Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, 10043 Turin, ItalyMitotane 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.https://www.mdpi.com/2072-6694/13/21/5255mitotaneadrenocortical carcinomaH295 strains |
| spellingShingle | Marco Lo Iacono Soraya Puglisi Paola Perotti Laura Saba Jessica Petiti Claudia Giachino Giuseppe Reimondo Massimo Terzolo Molecular Mechanisms of Mitotane Action in Adrenocortical Cancer Based on In Vitro Studies Cancers mitotane adrenocortical carcinoma H295 strains |
| title | Molecular Mechanisms of Mitotane Action in Adrenocortical Cancer Based on In Vitro Studies |
| title_full | Molecular Mechanisms of Mitotane Action in Adrenocortical Cancer Based on In Vitro Studies |
| title_fullStr | Molecular Mechanisms of Mitotane Action in Adrenocortical Cancer Based on In Vitro Studies |
| title_full_unstemmed | Molecular Mechanisms of Mitotane Action in Adrenocortical Cancer Based on In Vitro Studies |
| title_short | Molecular Mechanisms of Mitotane Action in Adrenocortical Cancer Based on In Vitro Studies |
| title_sort | molecular mechanisms of mitotane action in adrenocortical cancer based on in vitro studies |
| topic | mitotane adrenocortical carcinoma H295 strains |
| url | https://www.mdpi.com/2072-6694/13/21/5255 |
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