Strong enhancement by IGF1-R antagonists of hepatocellular carcinoma cell migration inhibition by Sorafenib and/or vitamin K1

Rosalba D'Alessandro, Maria Grazia Refolo, Catia Lippolis, Nicola Carella, Caterina Messa, Aldo Cavallini, Brian Irving Carr

Research output: Contribution to journalArticle

Abstract

PURPOSE: Emerging evidence indicates that combining Sorafenib with vitamin K1 (VK1) may result in a synergistic inhibition of hepatocellular carcinoma (HCC) cell migration and proliferation. Despite this synergy, its benefits may be limited due to drug resistance resulting from cross-talk with the tumor microenvironment. Insulin-like growth factor-1 (IGF1) signaling acts as an important modulator of HCC cell growth, motility and drug resistance. Therefore, we aimed to explore the effects of Sorafenib in combination with VK1 and/or IGF1-R antagonists on HCC cells.

METHODS: Scratch wound migration assays were performed to assess the motility of HCC-derived PLC/PRF/5, HLF and Hep3B cells. The synergistic, additive or antagonistic effects of Sorafenib, VK1 and IGF1-R antagonists on HCC cell motility were assessed using CompuSyn software. The effects mediated by these various compounds on HCC cytoskeleton organization were evaluated using DyLight 554 Phalloidin staining. Proliferation and migration-associated signaling pathways were analyzed in PLC/PRF/5 cells using Erk1/2 and Akt activation kits and Western blotting (Mek, JNK, Akt, Paxillin and p38), respectively.

RESULTS: The effects of the IGF1-R antagonists GSK1838705A and OSI-906 on HCC cell migration inhibition after Sorafenib and/or VK1 administration, individually or in combination, were evaluated. We found a synergistic effect in PLC/PRF/5, HLF and Hep3B cells for combinations of fixed doses of GSK1838705A or OSI-906 together with different doses of Sorafenib and/or VK1. The levels of synergy were found to be stronger at higher Sorafenib and/or VK1 concentrations and lower or absent at lower concentrations, with some variation among the different cell lines tested. In addition, we found that in PLC/PRF/5 and HLF cells IGF1-R blockage strongly enhanced the reduction and redistribution of F-actin induced by Sorafenib and/or VK1 through alterations in the phosphorylation levels of some of the principal proteins involved in the MAPK signaling cascade, which is essential for cell migration.

CONCLUSIONS: Our results indicate that modulation of the efficacy of Sorafenib through combinations with VK1 and/or IGF1-R antagonists results in synergistic inhibition of HCC cell migration.

Original languageEnglish
Pages (from-to)283-296
Number of pages14
JournalCellular oncology (Dordrecht)
Volume41
Issue number3
DOIs
Publication statusPublished - Jun 2018

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Cell Migration Inhibition
Vitamin K 1
Somatomedins
Hepatocellular Carcinoma
Cell Movement
Drug Resistance
Paxillin
Phalloidine
Tumor Microenvironment
sorafenib
Cytoskeleton
Actins
Software
Western Blotting
Phosphorylation
Cell Proliferation
Staining and Labeling
Cell Line

Keywords

  • Actin Cytoskeleton/pathology
  • Antineoplastic Combined Chemotherapy Protocols/pharmacology
  • Carcinoma, Hepatocellular/drug therapy
  • Cell Line, Tumor
  • Cell Movement/drug effects
  • Cell Proliferation
  • Extracellular Signal-Regulated MAP Kinases/metabolism
  • Humans
  • Imidazoles/pharmacology
  • Insulin-Like Growth Factor I/antagonists & inhibitors
  • Liver Neoplasms/drug therapy
  • Niacinamide/analogs & derivatives
  • Phenylurea Compounds/pharmacology
  • Phosphorylation
  • Protein Kinase Inhibitors/pharmacology
  • Pyrazines/pharmacology
  • Pyrimidines/pharmacology
  • Pyrroles/pharmacology
  • Sorafenib
  • Vitamin K 1/pharmacology

Cite this

Strong enhancement by IGF1-R antagonists of hepatocellular carcinoma cell migration inhibition by Sorafenib and/or vitamin K1. / D'Alessandro, Rosalba; Refolo, Maria Grazia; Lippolis, Catia; Carella, Nicola; Messa, Caterina; Cavallini, Aldo; Carr, Brian Irving.

In: Cellular oncology (Dordrecht), Vol. 41, No. 3, 06.2018, p. 283-296.

Research output: Contribution to journalArticle

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abstract = "PURPOSE: Emerging evidence indicates that combining Sorafenib with vitamin K1 (VK1) may result in a synergistic inhibition of hepatocellular carcinoma (HCC) cell migration and proliferation. Despite this synergy, its benefits may be limited due to drug resistance resulting from cross-talk with the tumor microenvironment. Insulin-like growth factor-1 (IGF1) signaling acts as an important modulator of HCC cell growth, motility and drug resistance. Therefore, we aimed to explore the effects of Sorafenib in combination with VK1 and/or IGF1-R antagonists on HCC cells.METHODS: Scratch wound migration assays were performed to assess the motility of HCC-derived PLC/PRF/5, HLF and Hep3B cells. The synergistic, additive or antagonistic effects of Sorafenib, VK1 and IGF1-R antagonists on HCC cell motility were assessed using CompuSyn software. The effects mediated by these various compounds on HCC cytoskeleton organization were evaluated using DyLight 554 Phalloidin staining. Proliferation and migration-associated signaling pathways were analyzed in PLC/PRF/5 cells using Erk1/2 and Akt activation kits and Western blotting (Mek, JNK, Akt, Paxillin and p38), respectively.RESULTS: The effects of the IGF1-R antagonists GSK1838705A and OSI-906 on HCC cell migration inhibition after Sorafenib and/or VK1 administration, individually or in combination, were evaluated. We found a synergistic effect in PLC/PRF/5, HLF and Hep3B cells for combinations of fixed doses of GSK1838705A or OSI-906 together with different doses of Sorafenib and/or VK1. The levels of synergy were found to be stronger at higher Sorafenib and/or VK1 concentrations and lower or absent at lower concentrations, with some variation among the different cell lines tested. In addition, we found that in PLC/PRF/5 and HLF cells IGF1-R blockage strongly enhanced the reduction and redistribution of F-actin induced by Sorafenib and/or VK1 through alterations in the phosphorylation levels of some of the principal proteins involved in the MAPK signaling cascade, which is essential for cell migration.CONCLUSIONS: Our results indicate that modulation of the efficacy of Sorafenib through combinations with VK1 and/or IGF1-R antagonists results in synergistic inhibition of HCC cell migration.",
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author = "Rosalba D'Alessandro and Refolo, {Maria Grazia} and Catia Lippolis and Nicola Carella and Caterina Messa and Aldo Cavallini and Carr, {Brian Irving}",
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volume = "41",
pages = "283--296",
journal = "Cellular oncology (Dordrecht)",
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TY - JOUR

T1 - Strong enhancement by IGF1-R antagonists of hepatocellular carcinoma cell migration inhibition by Sorafenib and/or vitamin K1

AU - D'Alessandro, Rosalba

AU - Refolo, Maria Grazia

AU - Lippolis, Catia

AU - Carella, Nicola

AU - Messa, Caterina

AU - Cavallini, Aldo

AU - Carr, Brian Irving

PY - 2018/6

Y1 - 2018/6

N2 - PURPOSE: Emerging evidence indicates that combining Sorafenib with vitamin K1 (VK1) may result in a synergistic inhibition of hepatocellular carcinoma (HCC) cell migration and proliferation. Despite this synergy, its benefits may be limited due to drug resistance resulting from cross-talk with the tumor microenvironment. Insulin-like growth factor-1 (IGF1) signaling acts as an important modulator of HCC cell growth, motility and drug resistance. Therefore, we aimed to explore the effects of Sorafenib in combination with VK1 and/or IGF1-R antagonists on HCC cells.METHODS: Scratch wound migration assays were performed to assess the motility of HCC-derived PLC/PRF/5, HLF and Hep3B cells. The synergistic, additive or antagonistic effects of Sorafenib, VK1 and IGF1-R antagonists on HCC cell motility were assessed using CompuSyn software. The effects mediated by these various compounds on HCC cytoskeleton organization were evaluated using DyLight 554 Phalloidin staining. Proliferation and migration-associated signaling pathways were analyzed in PLC/PRF/5 cells using Erk1/2 and Akt activation kits and Western blotting (Mek, JNK, Akt, Paxillin and p38), respectively.RESULTS: The effects of the IGF1-R antagonists GSK1838705A and OSI-906 on HCC cell migration inhibition after Sorafenib and/or VK1 administration, individually or in combination, were evaluated. We found a synergistic effect in PLC/PRF/5, HLF and Hep3B cells for combinations of fixed doses of GSK1838705A or OSI-906 together with different doses of Sorafenib and/or VK1. The levels of synergy were found to be stronger at higher Sorafenib and/or VK1 concentrations and lower or absent at lower concentrations, with some variation among the different cell lines tested. In addition, we found that in PLC/PRF/5 and HLF cells IGF1-R blockage strongly enhanced the reduction and redistribution of F-actin induced by Sorafenib and/or VK1 through alterations in the phosphorylation levels of some of the principal proteins involved in the MAPK signaling cascade, which is essential for cell migration.CONCLUSIONS: Our results indicate that modulation of the efficacy of Sorafenib through combinations with VK1 and/or IGF1-R antagonists results in synergistic inhibition of HCC cell migration.

AB - PURPOSE: Emerging evidence indicates that combining Sorafenib with vitamin K1 (VK1) may result in a synergistic inhibition of hepatocellular carcinoma (HCC) cell migration and proliferation. Despite this synergy, its benefits may be limited due to drug resistance resulting from cross-talk with the tumor microenvironment. Insulin-like growth factor-1 (IGF1) signaling acts as an important modulator of HCC cell growth, motility and drug resistance. Therefore, we aimed to explore the effects of Sorafenib in combination with VK1 and/or IGF1-R antagonists on HCC cells.METHODS: Scratch wound migration assays were performed to assess the motility of HCC-derived PLC/PRF/5, HLF and Hep3B cells. The synergistic, additive or antagonistic effects of Sorafenib, VK1 and IGF1-R antagonists on HCC cell motility were assessed using CompuSyn software. The effects mediated by these various compounds on HCC cytoskeleton organization were evaluated using DyLight 554 Phalloidin staining. Proliferation and migration-associated signaling pathways were analyzed in PLC/PRF/5 cells using Erk1/2 and Akt activation kits and Western blotting (Mek, JNK, Akt, Paxillin and p38), respectively.RESULTS: The effects of the IGF1-R antagonists GSK1838705A and OSI-906 on HCC cell migration inhibition after Sorafenib and/or VK1 administration, individually or in combination, were evaluated. We found a synergistic effect in PLC/PRF/5, HLF and Hep3B cells for combinations of fixed doses of GSK1838705A or OSI-906 together with different doses of Sorafenib and/or VK1. The levels of synergy were found to be stronger at higher Sorafenib and/or VK1 concentrations and lower or absent at lower concentrations, with some variation among the different cell lines tested. In addition, we found that in PLC/PRF/5 and HLF cells IGF1-R blockage strongly enhanced the reduction and redistribution of F-actin induced by Sorafenib and/or VK1 through alterations in the phosphorylation levels of some of the principal proteins involved in the MAPK signaling cascade, which is essential for cell migration.CONCLUSIONS: Our results indicate that modulation of the efficacy of Sorafenib through combinations with VK1 and/or IGF1-R antagonists results in synergistic inhibition of HCC cell migration.

KW - Actin Cytoskeleton/pathology

KW - Antineoplastic Combined Chemotherapy Protocols/pharmacology

KW - Carcinoma, Hepatocellular/drug therapy

KW - Cell Line, Tumor

KW - Cell Movement/drug effects

KW - Cell Proliferation

KW - Extracellular Signal-Regulated MAP Kinases/metabolism

KW - Humans

KW - Imidazoles/pharmacology

KW - Insulin-Like Growth Factor I/antagonists & inhibitors

KW - Liver Neoplasms/drug therapy

KW - Niacinamide/analogs & derivatives

KW - Phenylurea Compounds/pharmacology

KW - Phosphorylation

KW - Protein Kinase Inhibitors/pharmacology

KW - Pyrazines/pharmacology

KW - Pyrimidines/pharmacology

KW - Pyrroles/pharmacology

KW - Sorafenib

KW - Vitamin K 1/pharmacology

U2 - 10.1007/s13402-018-0370-z

DO - 10.1007/s13402-018-0370-z

M3 - Article

C2 - 29470830

VL - 41

SP - 283

EP - 296

JO - Cellular oncology (Dordrecht)

JF - Cellular oncology (Dordrecht)

SN - 2211-3428

IS - 3

ER -