Effect of combined treatment with a pan-PI3K inhibitor or an isoform-specific PI3K inhibitor and everolimus on cell prol
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ORIGINAL ARTICLE
Effect of combined treatment with a pan-PI3K inhibitor or an isoform-specific PI3K inhibitor and everolimus on cell proliferation in GH-secreting pituitary tumour in an experimental setting Claudia Pivonello1 Roberta Patalano1 Domenico Solari2 Renata S. Auriemma1 Federico Frio2 Francesca Vitulli2 Ludovica F. S. Grasso1 Marialuisa Di Cera1 Maria Cristina De Martino1 Luigi M. Cavallo2 Paolo Cappabianca2 Annamaria Colao1 Rosario Pivonello1 ●
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Received: 8 May 2017 / Accepted: 2 July 2018 © Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract Purpose PI3K/Akt/mTOR pathway activation is common in GH-secreting pituitary tumours, and a target for treatment with mTOR inhibitors, including everolimus (EVE). The current study aimed to evaluate the efficacy of two PI3K inhibitors (PI3Ki), NVP-BKM120 and NVP-BYL719, alone and in combination with EVE in rat GH-secreting pituitary tumour cell line (GH3) and human GH-secreting pituitary tumour cell cultures. Methods In GH3 cell line and in six GH-secreting tumour cell cultures, the effects of PI3Ki and EVE, as single agents and in combination, were tested on cell viability and colony survival, by MTT and clonogenic assay, respectively, whereas western blot was performed to evaluate the underlying intracellular signalling pathways. Results PI3Ki and EVE showed a dose-dependent inhibition of cell viability in GH3 cell line, with PI3Ki displaying a synergistic effect when combined with EVE. PI3Ki and EVE inhibited colony survival in GH3 cell line with no further improvement in combination. In GH-secreting pituitary tumour cell cultures PI3Ki are effective in inhibiting cell viability increasing the slight and non significant inhibition induced by EVE as single agent, generally showing a synergistic effect. Despite in both GH3 cell line and GH-secreting pituitary tumour cell cultures combination of PI3Ki enhanced EVE effect, the study of intracellular signalling pathways revealed a different regulation of PI3K/Akt/mTOR and MAPK between the two models. Conclusions The results of the current study demonstrated that PI3Ki, especially in combination with EVE, are effective in inhibiting cell proliferation, therefore representing a promising therapeutic tool for the treatment of aggressive GH-secreting pituitary tumours, not responsive to standard medical therapies. Keywords PI3K mTOR Everolimus GH-secreting pituitary adenoma NVP-BKM120. ●
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Introduction
These authors contributed equally: Claudia Pivonello, Roberta Patalano. * Claudia Pivonello [email protected] 1
Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Naples, Italy
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Dipartimento di Neuroscienze, Divisione di Neurochirurgia, Scienze Riproduttive e Odontostomatologiche, Naples, Italy
GH-secreting pituitary tumours are responsible for the development of acromegaly, a chronic disease characterised by the excess of GH and IGF-I, which induces an increase in morbidity and mortality, m
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