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Effects of the single and combined treatment with dopamine agonist, somatostatin analog and mTOR inhibitors in a human lung carcinoid cell line: an in vitro study

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Abstract

Somatostatin analogues and mTOR inhibitors have been used as medical therapy in lung carcinoids with variable results. No data are available on dopamine agonists as treatment for lung carcinoids. The main aim of the current study was to evaluate the effect of the combined treatment of somatostatin analogue octreotide and the dopamine agonist cabergoline with mTOR inhibitors in an in vitro model of typical lung carcinoids: the NCI-H727 cell line. In NCI-H727 cell line, reverse transcriptase-quantitative polymerase chain reaction and immunofluorescence were assessed to characterize the expression of the somatostatin receptor 2 and 5, dopamine receptor 2 and mTOR pathway components. Fifteen typical lung carcinoids tissue samples have been used for somatostatin receptor 2, dopamine receptor 2, and the main mTOR pathway component p70S6K expression and localization by immunohistochemistry. Cell viability, fluorescence-activated cell sorting analysis and western blot have been assessed to test the pharmacological effects of octreotide, cabergoline and mTOR inhibitors, and to evaluate the activation of specific cell signaling pathways in NCI-H727 cell line. NCI-H727 cell line expressed somatostatin receptor 2, somatostatin receptor 5 and dopamine receptor 2 and all mTOR pathway components at messenger and protein levels. Somatostatin receptor 2, dopamine receptor 2, and p70S6K (non phosphorylated and phosphorylated) proteins were expressed in most typical lung carcinoids tissue samples. Octreotide and cabergoline did not reduce cell viability as single agents but, when combined with mTOR inhibitors, they potentiate mTOR inhibitors effect after long-term exposure, reducing Akt and ERK phosphorylation, mTOR escape mechanisms, and increasing the expression DNA-damage-inducible transcript 4, an mTOR suppressor. In conclusion, the single use of octreotide and cabergoline is not sufficient to block cell viability but the combined approach of these agents with mTOR inhibitors might reduce the mTOR inhibitors-induced escape mechanisms and/or activate the endogenous mTOR suppressor, potentiating the effect of the mTOR inhibitors in an in vitro model of typical lung carcinoids.

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Author notes

    Authors and Affiliations

    1. Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples, 80131, Italy

      Claudia Pivonello, Mariarosaria Negri, Maddalena Sarnataro, Roberta Patalano, Maria Cristina De Martino, Concetta Sciammarella, Antongiulio Faggiano, Annamaria Colao & Rosario Pivonello

    2. Endocrine Unit, Department of Pathophysiology, University of Athens, Medical School, Laiko Hospital, Athens, Greece

      Panagoula Rousaki & Gregory A. Kaltsas

    3. Immunology Oncology Unit, National Cancer Institute ‘G. Pascale’ (IRCCS), Naples, Italy

      Maria Napolitano

    4. Pathology Unit, National Cancer Institute ‘G. Pascale’ (IRCCS), Naples, Italy

      Federica Zito Marino

    5. Division of Thoracic Surgery, Department of Thoracic Surgical and Medical Oncology, National Cancer Institute ‘G. Pascale’ (IRCCS), Naples, Italy

      Gaetano Rocco

    6. Pathology Unit, Second University of Naples - SUN, Naples, Italy

      Renato Franco

    Authors
    1. Claudia Pivonello
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    2. Panagoula Rousaki
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    3. Mariarosaria Negri
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    4. Maddalena Sarnataro
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    5. Maria Napolitano
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    6. Federica Zito Marino
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    7. Roberta Patalano
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    8. Maria Cristina De Martino
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    9. Concetta Sciammarella
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    10. Antongiulio Faggiano
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    11. Gaetano Rocco
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    12. Renato Franco
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    13. Gregory A. Kaltsas
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    14. Annamaria Colao
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    15. Rosario Pivonello
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    Corresponding author

    Correspondence to Rosario Pivonello.

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    Conflict of interest

    A.C. has been Principal Investigator of Research studies for Novartis, Ipsen, and Pfizer; received research grants from Novartis, Ipsen, Pfizer, Ferring, Lilly, Novo Nordisk, HRA Pharma, and Italfarmaco; has been an occasional consultant for Novartis, Ipsen, Pfizer, and Italfarmaco; and has received fees and honoraria for presentations from Novartis and Ipsen. R.P. has been Principal Investigator of Research Studies for Novartis; received research grants from Novartis, Pfizer, HRA Pharma, and Viropharma; has been an occasional consultant for Novartis, Ipsen, Pfizer, Viropharma, Ferring, and Italfarmaco; and has received fees and honoraria for presentations from Novartis.

    Additional information

    Claudia Pivonello and Panagoula Rousaki have contributed equally to this work

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    Pivonello, C., Rousaki, P., Negri, M. et al. Effects of the single and combined treatment with dopamine agonist, somatostatin analog and mTOR inhibitors in a human lung carcinoid cell line: an in vitro study. Endocrine 56, 603–620 (2017). https://doi.org/10.1007/s12020-016-1079-2

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    • DOI: https://doi.org/10.1007/s12020-016-1079-2

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