TY - JOUR
T1 - Metformin and everolimus: A promising combination for neuroendocrine tumors treatment
AU - Vitali, E.
AU - Boemi, I.
AU - Tarantola, G.
AU - Piccini, S.
AU - Zerbi, A.
AU - Veronesi, G.
AU - Baldelli, R.
AU - Mazziotti, G.
AU - Smiroldo, V.
AU - Lavezzi, E.
AU - Spada, A.
AU - Mantovani, G.
AU - Lania, A.G.
N1 - Export Date: 11 March 2021
Correspondence Address: Vitali, E.; Laboratory of Cellular and Molecular Endocrinology, Italy; email: eleonora.vitali@humanitasresearch.it
Correspondence Address: Vitali, E.; Department of Biomedical Sciences, Italy; email: eleonora.vitali@humanitasresearch.it
Chemicals/CAS: everolimus, 159351-69-6; metformin, 1115-70-4, 657-24-9; protein kinase B, 148640-14-6
Funding details: Ministero dell’Istruzione, dell’Università e della Ricerca, MIUR, PRIN 2017Z3N3YC
Funding text 1: Funding: This research was funded by The Ministry of Education, University and Research, grant number [PRIN 2017Z3N3YC] and the APC was funded by [PRIN 2017Z3N3YC].
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Everolimus
KW - Metformin
KW - Neuroendocrine tumors
KW - Resistance
KW - everolimus
KW - mammalian target of rapamycin
KW - metformin
KW - protein kinase B
KW - antineoplastic activity
KW - apoptosis
KW - Article
KW - cell proliferation
KW - cell viability
KW - colony formation
KW - controlled study
KW - drug efficacy
KW - drug mechanism
KW - enzyme phosphorylation
KW - flow cytometry
KW - growth rate
KW - human
KW - human cell
KW - immunoblotting
KW - monotherapy
KW - NCI-H727 cell line
KW - neuroendocrine tumor
KW - neuroendocrine tumor cell line
KW - pancreas islet cell tumor
KW - protein phosphorylation
KW - QGP-1 cell line
KW - tumor spheroid
U2 - 10.3390/cancers12082143
DO - 10.3390/cancers12082143
M3 - Article
VL - 12
SP - 1
EP - 18
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 8
ER -