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.
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.
Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples, 80131, Italy.
Claudia
C
Pivonello
Endocrine Unit, Department of Pathophysiology, University of Athens, Medical School, Laiko Hospital, Athens, Greece.
Panagoula
P
Rousaki
Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples, 80131, Italy.
Mariarosaria
M
Negri
Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples, 80131, Italy.
Maddalena
M
Sarnataro
Immunology Oncology Unit, National Cancer Institute 'G. Pascale' (IRCCS), Naples, Italy.
Maria
M
Napolitano
Pathology Unit, National Cancer Institute 'G. Pascale' (IRCCS), Naples, Italy.
Federica Zito
FZ
Marino
Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples, 80131, Italy.
Roberta
R
Patalano
Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples, 80131, Italy.
Maria Cristina
MC
De Martino
Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples, 80131, Italy.
Concetta
C
Sciammarella
Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples, 80131, Italy.
Antongiulio
A
Faggiano
Division of Thoracic Surgery, Department of Thoracic Surgical and Medical Oncology, National Cancer Institute 'G. Pascale' (IRCCS), Naples, Italy.
Gaetano
G
Rocco
Pathology Unit, Second University of Naples - SUN, Naples, Italy.
Renato
R
Franco
Endocrine Unit, Department of Pathophysiology, University of Athens, Medical School, Laiko Hospital, Athens, Greece.
Gregory A
GA
Kaltsas
Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples, 80131, Italy.
Annamaria
A
Colao
Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples, 80131, Italy. rosario.pivonello@unina.it.
Rosario
R
Pivonello
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000077465:Cabergoline; D002276:Carcinoid Tumor / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D018491:Dopamine Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004873:Ergolines / Q000494:pharmacology / Q000627:therapeutic use; D000068338:Everolimus / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015282:Octreotide / Q000494:pharmacology / Q000627:therapeutic use; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013004:Somatostatin / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; C581293:DRD2 protein, human; D018491:Dopamine Agonists; D004873:Ergolines; D017448:Receptors, Dopamine D2; D017481:Receptors, Somatostatin; D013004:Somatostatin; C094573:somatostatin receptor 5; D000068338:Everolimus; C093733:somatostatin receptor 2; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000077465:Cabergoline; D015282:Octreotide
Cabergoline; Dopamine receptors; Everolimus; Lung carcinoids; Octreotide; Somatostatin analogues; mTOR pathway
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