Metformin and everolimus: A promising combination for neuroendocrine tumors treatment

E. Vitali, I. Boemi, G. Tarantola, S. Piccini, A. Zerbi, G. Veronesi, R. Baldelli, G. Mazziotti, V. Smiroldo, E. Lavezzi, A. Spada, G. Mantovani, A.G. Lania

Research output: Contribution to journalArticlepeer-review


Introduction: Treatment options for neuroendocrine tumors (NETs) are rarely curative, as NETs frequently show resistance to medical therapy. The use of everolimus, an mTOR inhibitor, is limited by the development of resistance, probably due to the activation of Akt signaling. In this context, the antidiabetic drug metformin is able to inhibit mTOR, providing a rationale for the use of metformin and everolimus in combination. Methods: We investigated the effects of the metformin and everolimus combination on NET cell proliferation, apoptosis, colony formation, cell viability, NET spheroids growth and the involvement of the Akt and mTOR pathways, and also developed everolimus-resistant NET cells to further study this combination. Results: Metformin and everolimus in combination are more effective than monotherapy in inhibiting pancreatic NET (PAN-NET) cell proliferation (−71% ± 13%, p < 0.0001 vs. basal), whereas no additive effects were observed on pulmonary neuroendocrine tumor (PNT) cell proliferation. The combinatorial treatment is more effective than monotherapy in inhibiting colony formation, cell viability, NET spheroids growth rate and mTOR phosphorylation in both NET cell lines. In a PAN-NET cell line, metformin did not affect Akt phosphorylation; conversely, it significantly decreased Akt phosphorylation in a PNT cell line. Using everolimus-resistant NET cells, we confirmed that metformin maintained its effects, acting by two different pathways: Akt-dependent or independent, depending on the cell type, with both leading to mTOR suppression. Conclusions: Considering the promising effects of the everolimus and metformin combination in NET cells, our results provide a rationale for its use in NET patients. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Original languageEnglish
Pages (from-to)1-18
Number of pages18
Issue number8
Publication statusPublished - 2020


  • Everolimus
  • Metformin
  • Neuroendocrine tumors
  • Resistance
  • everolimus
  • mammalian target of rapamycin
  • metformin
  • protein kinase B
  • antineoplastic activity
  • apoptosis
  • Article
  • cell proliferation
  • cell viability
  • colony formation
  • controlled study
  • drug efficacy
  • drug mechanism
  • enzyme phosphorylation
  • flow cytometry
  • growth rate
  • human
  • human cell
  • immunoblotting
  • monotherapy
  • NCI-H727 cell line
  • neuroendocrine tumor
  • neuroendocrine tumor cell line
  • pancreas islet cell tumor
  • protein phosphorylation
  • QGP-1 cell line
  • tumor spheroid


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