Potentiating the Efficacy of Molecular Targeted Therapy for Hepatocellular Carcinoma by Inhibiting the Insulin-Like Growth Factor Pathway

Ou, Da‐Liang; Lee, Bin-Shyun; Chang, Ya-Chi; Lin, Liang-In; Liou, Jun‐Yang; Hsu, Chiun; Cheng, Ann‐Lii

doi:10.1371/journal.pone.0066589

Cited by 11 publications

(10 citation statements)

References 38 publications

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“…This combination of treatments induced G 2 /M cell cycle arrest, maintained IGF-1R, AKT, and ERK activation, but failed to induce apoptosis. Accordingly, IGF-1R/AKT pathway inhibition has been shown to improve the efficacy of molecular-targeted therapies such as sunitinib for HCC 45. Although sorafenib targets B-Raf and C-Raf in the ERK signaling pathway, we observed that sorafenib did not inhibit ERK phosphorylation in cells with mutant KRAS , as previously shown 46.…”

Section: Discussionsupporting

confidence: 66%

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma

Jeannot¹,

Busser²,

Vanwonterghem³

et al. 2016

OTT

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Development of drug resistance limits the efficacy of targeted therapies. Alternative approaches using different combinations of therapeutic agents to inhibit several pathways could be a more effective strategy for treating cancer. The effects of the approved epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (gefitinib) or a multi-targeted kinase inhibitor (sorafenib) in combination with a histone deacetylase inhibitor (vorinostat) on cell proliferation, cell cycle distribution, apoptosis, and signaling pathway activation in human lung adenocarcinoma and hepatocarcinoma cells with wild-type EGFR and mutant KRAS were investigated. The effects of the synergistic drug combinations were also studied in human lung adenocarcinoma and hepatocarcinoma cells in vivo. The combination of gefitinib and vorinostat synergistically reduced cell growth and strongly induced apoptosis through inhibition of the insulin-like growth factor-1 receptor/protein kinase B (IGF-1R/AKT)-dependent signaling pathway. Moreover, the gefitinib and vorinostat combination strongly inhibited tumor growth in mice with lung adenocarcinoma or hepatocarcinoma tumor xenografts. In contrast, the combination of sorafenib and vorinostat did not inhibit cell proliferation compared to a single treatment and induced G2/M cell cycle arrest without apoptosis. The sorafenib and vorinostat combination sustained the IGF-1R-, AKT-, and mitogen-activated protein kinase-dependent signaling pathways. These results showed that there was synergistic cytotoxicity when vorinostat was combined with gefitinib for both lung adenocarcinoma and hepatocarcinoma with mutant KRAS in vitro and in vivo but that the combination of vorinostat with sorafenib did not show any benefit. These findings highlight the important role of the IGF-1R/AKT pathway in the resistance to targeted therapies and support the use of histone deacetylase inhibitors in combination with EGFR-tyrosine kinase inhibitors, especially for treating patients with mutant KRAS resistant to other treatments.

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Section: Discussionsupporting

confidence: 66%

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma

Jeannot¹,

Busser²,

Vanwonterghem³

et al. 2016

OTT

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“…The isobologram is formed by plotting the concentrations of each drug for 50 % inhibition (ED 50 ) on the x-and y-axis, respectively, and connecting them to draw a line segment, which is ED 50 isobologram. Combination data points that fall on, below, and above the line segment represent additivity, synergism, and antagonism, respectively [23].…”

Section: Drug Combination Analysismentioning

confidence: 99%

MK-2206 induces apoptosis of AML cells and enhances the cytotoxicity of cytarabine

Lin

Lai

et al. 2015

Med Oncol

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Genetic alterations in the PI3K/AKT cascade have been linked to various human cancers including acute myeloid leukemia (AML) and have emerged to be promising targets for treatment. In this study, we explored the molecular mechanism and clinical implication of a specific allosteric AKT inhibitor, MK-2206, in the treatment of AML. Four leukemia cell lines, MV-4-11, MOLM-13, OCI/AML3, and U937, were used. Apoptosis and cell cycle distribution were determined by flow cytometry analysis. Expression of anti-apoptotic protein family and glycogen synthase kinase 3b (GSK3b) signaling was determined by western blotting. Drug combination effects of MK-2206 with cytarabine were evaluated by cell proliferation assay, and the combination index values were calculated by CompuSyn software. MK-2206 had no effect on normal peripheral blood mononuclear cells, but induced G 1 -phase arrest and apoptosis in leukemia cells. Among anti-apoptotic Bcl-2 family members, only myeloid cell leukemia-1 (Mcl-1) was significantly suppressed. Mcl-1 suppression by MK-2206 was closely associated with decreased GSK3b phosphorylation at Ser9, an event leads to GSK3b activation. Furthermore, the effect of MK-2206 on Mcl-1 downregulation was abolished by GSK3b inhibitor, lithium chloride and proteasome inhibitor, MG-132, suggesting that MK-2206 acted through a GSK3b-mediated, proteasome-dependent protein degradation. In addition, co-administration of MK-2206 with cytarabine could enhance the cytotoxic efficacy of cytarabine in leukemia cell lines. In conclusion, we have demonstrated that MK-2206 is an active agent in AML and its efficacy as in combination with cytarabine is implicated.

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“…In the present study, PPP enhanced sorafenib-induced suppression of proliferation and motility in HCC cells. NVP-AEW541, another IGF-1R inhibitor, and sorafenib were previously shown to suppress cell proliferation and induce apoptosis synergistically ( 16 ). These data suggest that IGF-1R inhibitors and sorafenib suppress cell proliferation synergistically.…”

Section: Discussionmentioning

confidence: 99%

Picropodophyllin and sorafenib synergistically suppress the proliferation and motility of hepatocellular carcinoma cells

et al. 2014

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Resistance is one limitation of sorafenib in the treatment of hepatocellular carcinoma (HCC). Insulin-like growth factor-1 receptor (IGF-1R) is involved in cancer cell proliferation. To assess the potential synergistic antitumor effects of picropodophyllin (PPP), an IGF-1R inhibitor, HLF and PLC/PRL/5, HCC cells were treated with PPP alone or PPP in combination with sorafenib, a multikinase inhibitor. Normal human umbilical vein endothelial cells (HUVECs) were also used to analyze the antiangiogenic effects of the drugs. HCC cells and HUVECs were cultured on 96-well plates, and then treated with PPP, with and without the addition of sorafenib. A 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt assay and hematoxylin and eosin staining were then performed 48 h later. The HCC cells were also analyzed using scratch assays and hematoxylin and eosin staining after 48 h. The proliferation of HLF, PLC/PRF/5 and HUVEC cells was suppressed by the combination of 0.2 μM PPP and 3 μM sorafenib more effectively than by 10 μM sorafenib alone. The motility of HLF and PLC/PRF/5 cells was also suppressed to a greater extent with the combination of PPP at 0.2 μM and sorafenib at 3 μM than with sorafenib at 10 μM alone. The cells that had been treated with 0.2 μM PPP and 3 μM sorafenib also exhibited pyknotic nuclei, which is characteristic of apoptosis. In conclusion, PPP enhanced sorafenib-mediated suppression of proliferation and motility in HCC cells. Therefore, the combination of PPP and sorafenib may exert antitumor and antiangiogenic effects.

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Potentiating the Efficacy of Molecular Targeted Therapy for Hepatocellular Carcinoma by Inhibiting the Insulin-Like Growth Factor Pathway

Cited by 11 publications

References 38 publications

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma

Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma

MK-2206 induces apoptosis of AML cells and enhances the cytotoxicity of cytarabine

Picropodophyllin and sorafenib synergistically suppress the proliferation and motility of hepatocellular carcinoma cells

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