Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. S. Melmed, A. Colao, A. Barkan, M. Molitch, A.B. Grossman, D. Kleinberg et al., Guidelines for acromegaly management: an update. J. Clin. Endocrinol. Metab. 94, 1509–17 (2009).

    Article  CAS  Google Scholar 

  2. R.N. Clayton, Cardiovascular function in acromegaly. Endocr. Rev. 24, 272–7 (2003)

    Article  CAS  Google Scholar 

  3. R. Pivonello, R.S. Auriemma, L.F. Grasso, C. Pivonello, C. Simeoli, R. Patalano et al., Complications of acromegaly: cardiovascular, respiratory and metabolic comorbidities. Pituitary 20, 46–62 (2017).

    Article  Google Scholar 

  4. A. Colao, D. Ferone, P. Marzullo, G. Lombardi, Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr. Rev. 25, 102–52 (2004)

    Article  CAS  Google Scholar 

  5. L. Katznelson, E.R. Laws Jr., S. Melmed, M.E. Molitch, M.H. Murad, A. Utz et al., Acromegaly: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 99, 3933–51 (2014)

    Article  CAS  Google Scholar 

  6. A. Giustina, A. Barkan, F.F. Casanueva, F. Cavagnini, L. Frohman, K. Ho et al., Criteria for cure of acromegaly: a consensus statement. J. Clin. Endocrinol. Metab. 85, 526–9 (2000)

    CAS  PubMed  Google Scholar 

  7. E.R. Laws, G. Lanzino. Transsphenoidal Surgery. (Saunders - Elsevier, Philadelphia, 2010)

    Google Scholar 

  8. D. Solari, L.M. Cavallo, P. Cappabianca, Surgical approach to pituitary tumors. Handb. Clin. Neurol. 124, 291–301 (2014)

    Article  Google Scholar 

  9. A. Colao, R. Pivonello, C. Di Somma, S. Savastano, L.F. Grasso, G. Lombardi, Medical therapy of pituitary adenomas: effects on tumor shrinkage. Rev. Endocr. Metab. Disord. 10, 111–23 (2009)

    Article  CAS  Google Scholar 

  10. A. Giustina, M.R. Ambrosio, P. Beck Peccoz, F. Bogazzi, S. Cannavo, L. De Marinis et al., Use of Pegvisomant in acromegaly. An Italian Society of Endocrinology guideline. J. Endocrinol. Invest. 37, 1017–30 (2014)

    Article  CAS  Google Scholar 

  11. A. Colao, R.S. Auriemma, G. Lombardi, R. Pivonello, Resistance to somatostatin analogs in acromegaly. Endocr. Rev. 32, 247–71 (2011)

    Article  CAS  Google Scholar 

  12. M.R. Gadelha, L.E. Wildemberg, M.D. Bronstein, F. Gatto, D. Ferone, Somatostatin receptor ligands in the treatment of acromegaly. Pituitary 20, 100–8 (2017)

    Article  CAS  Google Scholar 

  13. C. Beauregard, U. Truong, J. Hardy, O. Serri, Long-term outcome and mortality after transsphenoidal adenomectomy for acromegaly. Clin. Endocrinol. 58, 86–91 (2003)

    Article  Google Scholar 

  14. G. Minniti, M.L. Jaffrain-Rea, V. Esposito, A. Santoro, G. Tamburrano, G. Cantore, Evolving criteria for post-operative biochemical remission of acromegaly: can we achieve a definitive cure? An audit of surgical results on a large series and a review of the literature. Endocr. Relat. Cancer 10, 611–9 (2003)

    Article  CAS  Google Scholar 

  15. F. Di Nicolantonio, S. Arena, J. Tabernero, S. Grosso, F. Molinari, T. Macarulla et al., Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J. Clin. Invest. 120, 2858–66 (2010)

    Article  Google Scholar 

  16. Y. Lin, X. Jiang, Y. Shen, M. Li, H. Ma, M. Xing et al., Frequent mutations and amplifications of the PIK3CA gene in pituitary tumors. Endocr. Relat. Cancer 16, 301–10 (2009)

    Article  CAS  Google Scholar 

  17. K.E. O’Reilly, F. Rojo, Q.B. She, D. Solit, G.B. Mills, D. Smith et al., mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66, 1500–8 (2006)

    Article  Google Scholar 

  18. I. Vivanco, C.L. Sawyers, The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2, 489–501 (2002)

    Article  CAS  Google Scholar 

  19. D.A. Altomare, J.R. Testa, Perturbations of the AKT signaling pathway in human cancer. Oncogene 24, 7455–64 (2005)

    Article  CAS  Google Scholar 

  20. K.H. Khan, T.A. Yap, L. Yan, D. Cunningham, Targeting the PI3K-AKT-mTOR signaling network in cancer. Chin. J. Cancer 32, 253–65 (2013)

    Article  CAS  Google Scholar 

  21. C. Pivonello, M. Negri, M.C. De Martino, M. Napolitano, C. de Angelis, D.P. Provvisiero et al., The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma. Oncotarget 7, 9718–31 (2016)

    Article  Google Scholar 

  22. L. Zhao, P.K. Vogt, Class I PI3K in oncogenic cellular transformation. Oncogene 27, 5486–96 (2008)

    Article  CAS  Google Scholar 

  23. T.L. Yuan, L.C. Cantley, PI3K pathway alterations in cancer: variations on a theme. Oncogene 27, 5497–510 (2008)

    Article  CAS  Google Scholar 

  24. A. Carracedo, L. Ma, J. Teruya-Feldstein, F. Rojo, L. Salmena, A. Alimonti et al., Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J. Clin. Investig. 118, 3065–74 (2008)

    CAS  PubMed  Google Scholar 

  25. E. Monsalves, K. Juraschka, T. Tateno, S. Agnihotri, S.L. Asa, S. Ezzat et al., The PI3K/AKT/mTOR pathway in the pathophysiology and treatment of pituitary adenomas. Endocr. Relat. Cancer 21, R331–44 (2014)

    Article  CAS  Google Scholar 

  26. S. Jean, A.A. Kiger, Classes of phosphoinositide 3-kinases at a glance. J. Cell. Sci. 127, 923–8 (2014)

    Article  CAS  Google Scholar 

  27. M. Chanal, P. Chevallier, V. Raverot, G. Fonteneau, K. Lucia, J.L. Monteserin Garcia et al., Differential effects of PI3K and dual PI3K/mTOR inhibition in rat prolactin-secreting pituitary tumors. Mol. Cancer Ther. 15, 1261–70 (2016)

    Article  CAS  Google Scholar 

  28. C.B. Murat, P.B. Braga, M.A. Fortes, M.D. Bronstein, M.L. Correa-Giannella, R.R. Giorgi, Mutation and genomic amplification of the PIK3CA proto-oncogene in pituitary adenomas. Braz. J. Med. Biol. Res. 45, 851–5 (2012)

    Article  CAS  Google Scholar 

  29. M. Cakir, A.B. Grossman, Targeting MAPK (Ras/ERK) and PI3K/Akt pathways in pituitary tumorigenesis. Expert. Opin. Ther. Targets 13, 1121–34 (2009)

    Article  CAS  Google Scholar 

  30. D. Dworakowska, E. Wlodek, C.A. Leontiou, S. Igreja, M. Cakir, M. Teng et al., Activation of RAF/MEK/ERK and PI3K/AKT/mTOR pathways in pituitary adenomas and their effects on downstream effectors. Endocr. Relat. Cancer 16, 1329–38 (2009)

    Article  CAS  Google Scholar 

  31. M. Musat, M. Korbonits, B. Kola, N. Borboli, M.R. Hanson, A.M. Nanzer et al., Enhanced protein kinase B/Akt signalling in pituitary tumours. Endocr. Relat. Cancer 12, 423–33 (2005)

    Article  CAS  Google Scholar 

  32. B. Svejda, M. Kidd, A. Kazberouk, B. Lawrence, R. Pfragner, I.M. Modlin, Limitations in small intestinal neuroendocrine tumor therapy by mTor kinase inhibition reflect growth factor-mediated PI3K feedback loop activation via ERK1/2 and AKT. Cancer 117, 4141–54 (2011)

    Article  CAS  Google Scholar 

  33. D.A. Cantrell, Phosphoinositide 3-kinase signalling pathways. J. Cell. Sci. 114, 1439–45 (2001)

    CAS  PubMed  Google Scholar 

  34. B.T. Hennessy, D.L. Smith, P.T. Ram, Y. Lu, G.B. Mills, Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev. Drug. Discov. 4, 988–1004 (2005)

    Article  CAS  Google Scholar 

  35. X. Bai, Y. Jiang, Key factors in mTOR regulation. Cell. Mol. Life Sci. 67, 239–53 (2010)

    Article  CAS  Google Scholar 

  36. R. Chen, J. Duan, L. Li, Q. Ma, Q. Sun, J. Ma et al., mTOR promotes pituitary tumor development through activation of PTTG1. Oncogene 36, 979–88 (2017)

    Article  CAS  Google Scholar 

  37. S.M. Maira, S. Pecchi, A. Huang, M. Burger, M. Knapp, D. Sterker et al., Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol. Cancer Ther. 11, 317–28 (2012)

    Article  CAS  Google Scholar 

  38. P. Furet, V. Guagnano, R.A. Fairhurst, P. Imbach-Weese, I. Bruce, M. Knapp et al., Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg. Med. Chem. Lett. 23, 3741–8 (2013)

    Article  CAS  Google Scholar 

  39. R.J. Motzer, B. Escudier, S. Oudard, T.E. Hutson, C. Porta, S. Bracarda et al., Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372, 449–56 (2008)

    Article  CAS  Google Scholar 

  40. A.X. Zhu, M. Kudo, E. Assenat, S. Cattan, Y.K. Kang, H.Y. Lim et al., Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA 312, 57–67 (2014)

    Article  Google Scholar 

  41. N. Wagle, B.C. Grabiner, E.M. Van Allen, A. Amin-Mansour, A. Taylor-Weiner, M. Rosenberg et al., Response and acquired resistance to everolimus in anaplastic thyroid cancer. N. Engl. J. Med. 371, 1426–33 (2014)

    Article  Google Scholar 

  42. M.E. Pavel, J.D. Hainsworth, E. Baudin, M. Peeters, D. Horsch, R.E. Winkler et al., Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 378, 2005–12 (2011)

    Article  CAS  Google Scholar 

  43. J.C. Yao, M.H. Shah, T. Ito, C.L. Bohas, E.M. Wolin, E. Van Cutsem et al., Everolimus for advanced pancreatic neuroendocrine tumors. N. Engl. J. Med. 364, 514–23 (2011)

    Article  CAS  Google Scholar 

  44. A. Gorshtein, H. Rubinfeld, E. Kendler, M. Theodoropoulou, V. Cerovac, G.K. Stalla et al., Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro. Endocr. Relat. Cancer 16, 1017–27 (2009)

    Article  CAS  Google Scholar 

  45. S. Sukumari-Ramesh, N. Singh, K.M. Dhandapani, J.R. Vender, mTOR inhibition reduces cellular proliferation and sensitizes pituitary adenoma cells to ionizing radiation. Surg. Neurol. Int. 2, 22 (2011)

    Article  Google Scholar 

  46. E. Rozengurt, H.P. Soares, J. Sinnet-Smith, Suppression of feedback loops mediated by PI3K/mTOR induces multiple overactivation of compensatory pathways: an unintended consequence leading to drug resistance. Mol. Cancer Ther. 13, 2477–88 (2014)

    Article  CAS  Google Scholar 

  47. G. Brabant, A. von zur Muhlen, C. Wuster, M.B. Ranke, J. Kratzsch, W. Kiess et al., Serum insulin-like growth factor I reference values for an automated chemiluminescence immunoassay system: results from a multicenter study. Horm. Res. 60, 53–60 (2003)

    CAS  PubMed  Google Scholar 

  48. C. Pivonello, P. Rousaki, M. Negri, M. Sarnataro, M. Napolitano, F.Z. Marino 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, 603–20 (2017)

    Article  CAS  Google Scholar 

  49. C. Desbois-Mouthon, A. Baron, M.J. Blivet-Van Eggelpoel, L. Fartoux, C. Venot, F. Bladt et al., Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin-like growth factor-1 receptor and epidermal growth factor receptor in hepatocellular carcinoma. Clin. Cancer Res. 15, 5445–56 (2009)

    Article  CAS  Google Scholar 

  50. D.A. Donoho, N. Bose, G. Zada, J.D. Carmichael, Management of aggressive growth hormone secreting pituitary adenomas. Pituitary 20, 169–78 (2017)

    Article  CAS  Google Scholar 

  51. E.A. Sajjad, G. Zielinski, M. Maksymowicz, L. Hutnik, T. Bednarczuk, P. Wlodarski, mTOR is frequently active in GH-secreting pituitary adenomas without influencing their morphopathological features. Endocr. Pathol. 24, 11–9 (2013)

    Article  CAS  Google Scholar 

  52. M. Lee, T. Wiedemann, C. Gross, I. Leinhauser, F. Roncaroli, R. Braren et al., Targeting PI3K/mTOR signaling displays potent antitumor efficacy against nonfunctioning pituitary adenomas. Clin. Cancer Res. 21, 3204–15 (2015)

    Article  CAS  Google Scholar 

  53. M. Lee, M. Theodoropoulou, J. Graw, F. Roncaroli, M.C. Zatelli, N.S. Pellegata, Levels of p27 sensitize to dual PI3K/mTOR inhibition. Mol. Cancer Ther. 10, 1450–9 (2011)

    Article  CAS  Google Scholar 

  54. H. Rubinfeld, I. Shimon, PI3K/Akt/mTOR and Raf/MEK/ERK signaling pathways perturbations in non-functioning pituitary adenomas. Endocrine 42, 285–91 (2012)

    Article  CAS  Google Scholar 

  55. J.D. Valentino, J. Li, Y.Y. Zaytseva, W.C. Mustain, V.A. Elliott, J.T. Kim et al., Cotargeting the PI3K and RAS pathways for the treatment of neuroendocrine tumors. Clin. Cancer Res. 20, 1212–22 (2014)

    Article  CAS  Google Scholar 

  56. S. Nolting, J. Rentsch, H. Freitag, K. Detjen, F. Briest, M. Mobs et al., The selective PI3Kalpha inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: results from multiple cell line models. PLoS ONE 12, e0182852 (2017)

    Article  Google Scholar 

  57. Y. Hu, R. Guo, J. Wei, Y. Zhou, W. Ji, J. Liu et al., Effects of PI3K inhibitor NVP-BKM120 on overcoming drug resistance and eliminating cancer stem cells in human breast cancer cells. Cell Death Dis. 6, e2020 (2015)

    Article  CAS  Google Scholar 

  58. Y. Zheng, J. Yang, J. Qian, L. Zhang, Y. Lu, H. Li et al., Novel phosphatidylinositol 3-kinase inhibitor NVP-BKM120 induces apoptosis in myeloma cells and shows synergistic anti-myeloma activity with dexamethasone. J. Mol. Med. 90, 695–706 (2012)

    Article  CAS  Google Scholar 

  59. E. Musi, G. Ambrosini, E. de Stanchina, G.K. Schwartz, The phosphoinositide 3-kinase alpha selective inhibitor BYL719 enhances the effect of the protein kinase C inhibitor AEB071 in GNAQ/GNA11-mutant uveal melanoma cells. Mol. Cancer Ther. 13, 1044–53 (2014)

    Article  CAS  Google Scholar 

  60. H. Ren, H. Guo, A. Thakur, S. Zhang, T. Wang, Y. Liang et al., Blockade efficacy of MEK/ERK-dependent autophagy enhances PI3K/Akt inhibitor NVP-BKM120’s therapeutic effectiveness in lung cancer cells. Oncotarget 7, 67277–87 (2016)

    PubMed  PubMed Central  Google Scholar 

  61. J.C. Bendell, J. Rodon, H.A. Burris, M. de Jonge, J. Verweij, D. Birle et al., Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 30, 282–90 (2012)

    Article  CAS  Google Scholar 

  62. S.S. De Buck, A. Jakab, M. Boehm, D. Bootle, D. Juric, C. Quadt et al., Population pharmacokinetics and pharmacodynamics of BYL719, a phosphoinositide 3-kinase antagonist, in adult patients with advanced solid malignancies. Br. J. Clin. Pharmacol. 78, 543–55 (2014)

    Article  Google Scholar 

  63. M.C. Zatelli, M. Minoia, C. Filieri, F. Tagliati, M. Buratto, M.R. Ambrosio et al., Effect of everolimus on cell viability in nonfunctioning pituitary adenomas. J. Clin. Endocrinol. Metab. 95, 968–76 (2010)

    Article  CAS  Google Scholar 

  64. V. Cerovac, J. Monteserin-Garcia, H. Rubinfeld, M. Buchfelder, M. Losa, T. Florio et al., The somatostatin analogue octreotide confers sensitivity to rapamycin treatment on pituitary tumor cells. Cancer Res. 70, 666–74 (2010)

    Article  CAS  Google Scholar 

  65. R. Loewith, E. Jacinto, S. Wullschleger, A. Lorberg, J.L. Crespo, D. Bonenfant et al., Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10, 457–68 (2002)

    Article  CAS  Google Scholar 

  66. S.C. Hanna, S.A. Heathcote, W.Y. Kim, mTOR pathway in renal cell carcinoma. Expert. Rev. AntiCancer Ther. 8, 283–92 (2008)

    Article  CAS  Google Scholar 

  67. A. O’Donnell, S. Faivre, H.A. Burris 3rd, D. Rea, V. Papadimitrakopoulou, N. Shand et al., Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J. Clin. Oncol.: Off. J. Am. Soc. Clin. Oncol. 26, 1588–95 (2008)

    Article  Google Scholar 

  68. C. Di Pasquale, E. Gentilin, S. Falletta, M. Bellio, M. Buratto, E. Degli Uberti et al. , PI3K/Akt/mTOR pathway involvement in regulating growth hormone secretion in a rat pituitary adenoma cell line. Endocrine 60, 308–316 (2018).

    Article  CAS  Google Scholar 

  69. R.J. Shaw, L.C. Cantley, Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441, 424–30 (2006)

    Article  CAS  Google Scholar 

  70. M. Breuleux, M. Klopfenstein, C. Stephan, C.A. Doughty, L. Barys, S.M. Maira et al., Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition. Mol. Cancer Ther. 8, 742–53 (2009)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by research grant from Novartis Pharma Italy and by Scientific Independence of young Researchers (SIR RBSI143JZM) grant 2014 from Italian Ministry of Education, University and Research.

Author information

Author notes

  1. These authors contributed equally: Claudia Pivonello, Roberta Patalano.

Authors and Affiliations

  1. Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Naples, Italy

    Claudia Pivonello, Roberta Patalano, Renata S. Auriemma, Ludovica F. S. Grasso, Marialuisa Di Cera, Maria Cristina De Martino, Annamaria Colao & Rosario Pivonello

  2. Dipartimento di Neuroscienze, Divisione di Neurochirurgia, Scienze Riproduttive e Odontostomatologiche, Naples, Italy

    Domenico Solari, Federico Frio, Francesca Vitulli, Luigi M. Cavallo & Paolo Cappabianca

Authors
  1. Claudia Pivonello
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roberta Patalano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Domenico Solari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Renata S. Auriemma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Federico Frio
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Francesca Vitulli
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ludovica F. S. Grasso
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marialuisa Di Cera
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maria Cristina De Martino
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Luigi M. Cavallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Paolo Cappabianca
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Annamaria Colao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Rosario Pivonello
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claudia Pivonello.

Ethics declarations

Conflict of interest

A.C. has been principal investigator of research studies from Novartis, Ipsen, Pfizer and Lilly, has received research grants from Ferring, Lilly, Ipsen, Merck-Serono, Novartis, Novo-Nordisk and Pfizer, has been occasional consultant for Novartis, Ipsen and Pfizer, and has received fees and honoraria from Ipsen, Novartis, and Pfizer. R.P. has been principal investigator of research studies from Novartis and HRA Pharma, has received research grants from Novartis, Ipsen, Pfizer, Viropharma and IBSA, has been occasional consultant for Novartis, Ipsen, Pfizer, Viropharma, Ferring and Italfarmaco, and received lecture fees and honoraria from Novartis, Pfizer and Shire. The remaining authors declare that they have no conflict of interest.

Ethics approval

All procedures performed in this study were in accordance with the ethical standards of the University Federico II of Naples (Naples, Italy) and with the 1964 Helsinki declaration and its later amendments.

Consent for publication

Informed consent was obtained from each patient.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pivonello, C., Patalano, R., Solari, D. et al. 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 . Endocrine 62, 663–680 (2018). https://doi.org/10.1007/s12020-018-1677-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-018-1677-2

Keywords

Search

Navigation