title: The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma.
abstract: Deregulation of mTOR and IGF pathways is frequent in hepatocellular carcinoma (HCC), thus mTOR and IGF1R represent suitable therapeutic targets in HCC. The aim of this study was to evaluate the effects of mTOR inhibitors (mTORi) and OSI-906, blocker of IGF1R/IR, on HCC cell proliferation, viability, migration and invasion, and alpha-fetoprotein (α-FP) secretion. In HepG2 and HuH-7 we evaluated, the expression of mTOR and IGF pathway components; the effects of Sirolimus, Everolimus, Temsirolimus and OSI-906 on cell proliferation; the effects of Sirolimus, OSI-906, and their combination, on cell secretion, proliferation, viability, cell cycle, apoptosis, invasion and migration. Moreover, intracellular mechanisms underlying these cell functions were evaluated in both cell lines. Our results show that HepG2 and HuH-7 present with the same mRNA expression profile with high levels of IGF2. OSI-906 inhibited cell proliferation at high concentration, while mTORi suppressed cell proliferation in a dose-time dependent manner in both cell lines. The co-treatment showed an additive inhibitory effect on cell proliferation and viability. This effect was not related to induction of apoptosis, but to G0/G1 phase block. Moreover, the co-treatment prevented the Sirolimus-induced AKT activation as escape mechanism. Both agents demonstrated to be differently effective in inhibiting α-FP secretion. Sirolimus, OSI-906, and their combination, blocked cell migration and invasion in HuH-7. These findings indicate that, co-targeting of IGF1R/IR and mTOR pathways could be a novel therapeutic approach in the management of HCC, in order to maximize antitumoral effect and to prevent the early development of resistance mechanisms.
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, Università "Federico II" di Napoli, Naples, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pivonello
authors.affiliation: IOS & Coleman Medicina Futura Medical Center, Centro Direzionale, Naples, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Negri
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, Università "Federico II" di Napoli, Naples, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: De Martino
authors.affiliation: Immunology Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" (IRCCS), Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Napolitano
authors.affiliation: IOS & Coleman Medicina Futura Medical Center, Centro Direzionale, Naples, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: de Angelis
authors.affiliation: IOS & Coleman Medicina Futura Medical Center, Centro Direzionale, Naples, Italy.
authors.forename: Donatella Paola
authors.initials: DP
authors.lastname: Provvisiero
authors.affiliation: IRCCS Fondazione SDN, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" (IRCCS), Naples, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Cuomo
authors.affiliation: IOS & Coleman Medicina Futura Medical Center, Centro Direzionale, Naples, Italy.
authors.forename: Renata Simona
authors.initials: RS
authors.lastname: Auriemma
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, Università "Federico II" di Napoli, Naples, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Simeoli
authors.affiliation: Hepatobiliary Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" (IRCCS), Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Izzo
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, Università "Federico II" di Napoli, Naples, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Colao
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, Università "Federico II" di Napoli, Naples, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Pivonello
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004338:Drug Combinations; D000068338:Everolimus / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000509:alpha-Fetoproteins / Q000378:metabolism*
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D000970:Antineoplastic Agents; D004338:Drug Combinations; C000597236:IGF1R protein, human; D007093:Imidazoles; D007328:Insulin; D011719:Pyrazines; D012333:RNA, Messenger; D017451:Receptors, Somatomedin; D000509:alpha-Fetoproteins; C401859:temsirolimus; D000068338:Everolimus; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020123:Sirolimus
keywords: HCC; IGF1R; OSI-906; mTOR