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Primary Culture of Rat Adrenocortical Cells and Assays of Steroidogenic Functions
Published on: March 12, 2019
Tissue Expression and Pharmacological In Vitro Analyses of mTOR and SSTR Pathways in Adrenocortical Carcinoma
Antonina Germano1, Ida Rapa1, Eleonora Duregon2
1Department of Clinical and Biological Sciences and Department of Oncology, University of Turin at San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, Turin, Italy.
Abstract:
New therapies for advanced adrenocortical carcinoma (ACC) are urgently needed, as the majority of the patients experience a rapid and inexorable progression despite surgery and adjuvant mitotane. In vitro data suggest that somatostatin receptors (SSTRs) and mTOR pathway might represent reasonable targets for novel therapies, being involved in functionality and growth of ACC cells. However, in vitro analysis of combination treatments targeting both mTOR and SSTR as compared to mitotane are poorly explored in ACC. This study aimed to investigate in vitro the effects on cell growth of pasireotide, everolimus, and mitotane, alone or combined, in the two ACC cell lines H295R and SW13 (mitotane sensitive and resistant, respectively). Moreover, the tissue expression of mTOR pathway molecules and SSTR (types 1-5) was assessed in 58 ACCs. In both cell lines, only everolimus induced a significant inhibition of cell growth. Conversely, the combinations among mitotane, pasireotide, and everolimus produced antagonistic effects on mitotane-induced growth inhibition on H295R cell line. A heterogeneous profile of mTOR-related molecules and SSTR expression was observed in ACC samples, being the mTOR pathway found activated in approximately 30% of cases. In conclusion, our data suggest caution in designing combinations of mitotane with other drugs potentially active in ACC, such as mTOR inhibitors or somatostatin analogs.
Insights
New therapies for adrenocortical carcinoma (ACC) are needed. Combination treatments with everolimus, pasireotide, and mitotane showed antagonistic effects, suggesting caution in drug combinations for ACC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Adrenocortical carcinoma (ACC) often progresses despite current treatments like surgery and mitotane.
- Somatostatin receptors (SSTRs) and the mTOR pathway are implicated in ACC cell growth and function.
- Limited in vitro data exist on combining mTOR inhibitors and SSTR analogs with mitotane in ACC.
Purpose of the Study:
- To investigate the in vitro effects of pasireotide, everolimus, and mitotane, alone and combined, on ACC cell lines.
- To assess the expression of mTOR pathway molecules and SSTRs (types 1-5) in human ACC tissues.
- To evaluate potential therapeutic strategies for advanced adrenocortical carcinoma.
Main Methods:
- In vitro cell growth assays using H295R (mitotane-sensitive) and SW13 (mitotane-resistant) ACC cell lines.
- Treatment with pasireotide, everolimus, and mitotane individually and in combination.
- Immunohistochemical analysis of mTOR pathway components and SSTRs in 58 ACC tissue samples.
Main Results:
- Everolimus significantly inhibited cell growth in both ACC cell lines.
- Combinations of mitotane with pasireotide and everolimus demonstrated antagonistic effects on mitotane-induced growth inhibition in H295R cells.
- A heterogeneous expression profile of mTOR pathway molecules and SSTRs was observed in ACC samples, with mTOR pathway activation in approximately 30% of cases.
Conclusions:
- Caution is advised when designing combination therapies involving mitotane with mTOR inhibitors or somatostatin analogs for ACC.
- Everolimus shows single-agent activity against ACC cell lines.
- Heterogeneous molecular profiles in ACC necessitate personalized therapeutic approaches.
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