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Liver cancer cells are sensitive to Lanatoside C induced cell death independent of their PTEN status

Hepatocellular carcinoma is the second deadliest cancer with limited treatment options. Loss of PTEN causes the P13K/Akt pathway to be hyperactive which contributes to cell survival and resistance to therapeutics in various cancers, including the liver cancer. Hence molecules targeting this pathway... Full description

Journal Title: Phytomedicine (Stuttgart) 2016-01-15, Vol.23 (1), p.42-51
Main Author: Durmaz, Irem
Other Authors: Guven, Ebru Bilget , Ersahin, Tulin , Ozturk, Mehmet , Calis, Ihsan , Cetin-Atalay, Rengul
Format: Electronic Article Electronic Article
Language: English
Subjects:
Akt
ERK
Quelle: Alma/SFX Local Collection
Publisher: Germany: Elsevier GmbH
ID: ISSN: 0944-7113
Link: https://www.ncbi.nlm.nih.gov/pubmed/26902406
Zum Text:
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recordid: cdi_proquest_miscellaneous_1767916494
title: Liver cancer cells are sensitive to Lanatoside C induced cell death independent of their PTEN status
format: Article
creator:
  • Durmaz, Irem
  • Guven, Ebru Bilget
  • Ersahin, Tulin
  • Ozturk, Mehmet
  • Calis, Ihsan
  • Cetin-Atalay, Rengul
subjects:
  • Akt
  • Animals
  • Apoptosis
  • Apoptosis - drug effects
  • Carcinoma, Hepatocellular - pathology
  • Cardiac glycosides
  • Cardiotonic agents
  • Care and treatment
  • Cell Line, Tumor
  • Cell Proliferation
  • Digitalis - chemistry
  • Dosage and administration
  • ERK
  • Health aspects
  • Hepatocellular carcinoma
  • Humans
  • Lanatoside C
  • Lanatosides - pharmacology
  • Liver cancer
  • Liver Neoplasms - pathology
  • Medicine, Botanic
  • Medicine, Herbal
  • Mice
  • Mice, Nude
  • Oxidative Stress
  • PTEN
  • PTEN Phosphohydrolase - metabolism
  • Signal Transduction
  • Xenograft Model Antitumor Assays
ispartof: Phytomedicine (Stuttgart), 2016-01-15, Vol.23 (1), p.42-51
description: Hepatocellular carcinoma is the second deadliest cancer with limited treatment options. Loss of PTEN causes the P13K/Akt pathway to be hyperactive which contributes to cell survival and resistance to therapeutics in various cancers, including the liver cancer. Hence molecules targeting this pathway present good therapeutic strategies for liver cancer. It was previously reported that Cardiac glycosides possessed antitumor activity by inducing apoptosis of multiple cancer cells through oxidative stress. However, whether Cardiac glycoside Lanatoside C can induce oxidative stress in liver cancer cells and induce cell death both in vitro and in vivo remains unknown. Cell viability was measured by SRB assay. Cell death analysis was investigated by propidium iodide staining with flow cytometry and PARP cleavage. DCFH-DA staining and cytometry were used for intracellular ROS measurement. Protein levels were analyzed by western blot analysis. Antitumor activity was investigated on mice xenografts in vivo. In this study, we found that Cardiac glycosides, particularly Lanatoside C from Digitalis ferruginea could significantly inhibit PTEN protein adequate Huh7 and PTEN deficient Mahlavu human liver cancer cell proliferation by the induction of apoptosis and G2/M arrest in the cells. Lanatoside C was further shown to induce oxidative stress and alter ERK and Akt pathways. Consequently, JNK1 activation resulted in extrinsic apoptotic pathway stimulation in both cells while JNK2 activation involved in the inhibition of cell survival only in PTEN deficient cells. Furthermore, nude mice xenografts followed by MRI showed that Lanatoside C caused a significant decrease in the tumor size. In this study apoptosis induction by Lanatoside C was characterized through ROS altered ERK and Akt pathways in both PTEN adequate epithelial and deficient mesenchymal liver cancer cells. The results indicated that Lanatoside C could be contemplated in liver cancer therapeutics, particularly in PTEN deficient tumors. This is due to Lanatoside C's stress inducing action on ERK and Akt pathways through differential activation of JNK1 and JNK2 by GSK3β. [Display omitted]
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0944-7113
fulltext: fulltext
issn:
  • 0944-7113
  • 1618-095X
url: Link


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descriptionHepatocellular carcinoma is the second deadliest cancer with limited treatment options. Loss of PTEN causes the P13K/Akt pathway to be hyperactive which contributes to cell survival and resistance to therapeutics in various cancers, including the liver cancer. Hence molecules targeting this pathway present good therapeutic strategies for liver cancer. It was previously reported that Cardiac glycosides possessed antitumor activity by inducing apoptosis of multiple cancer cells through oxidative stress. However, whether Cardiac glycoside Lanatoside C can induce oxidative stress in liver cancer cells and induce cell death both in vitro and in vivo remains unknown. Cell viability was measured by SRB assay. Cell death analysis was investigated by propidium iodide staining with flow cytometry and PARP cleavage. DCFH-DA staining and cytometry were used for intracellular ROS measurement. Protein levels were analyzed by western blot analysis. Antitumor activity was investigated on mice xenografts in vivo. In this study, we found that Cardiac glycosides, particularly Lanatoside C from Digitalis ferruginea could significantly inhibit PTEN protein adequate Huh7 and PTEN deficient Mahlavu human liver cancer cell proliferation by the induction of apoptosis and G2/M arrest in the cells. Lanatoside C was further shown to induce oxidative stress and alter ERK and Akt pathways. Consequently, JNK1 activation resulted in extrinsic apoptotic pathway stimulation in both cells while JNK2 activation involved in the inhibition of cell survival only in PTEN deficient cells. Furthermore, nude mice xenografts followed by MRI showed that Lanatoside C caused a significant decrease in the tumor size. In this study apoptosis induction by Lanatoside C was characterized through ROS altered ERK and Akt pathways in both PTEN adequate epithelial and deficient mesenchymal liver cancer cells. The results indicated that Lanatoside C could be contemplated in liver cancer therapeutics, particularly in PTEN deficient tumors. This is due to Lanatoside C's stress inducing action on ERK and Akt pathways through differential activation of JNK1 and JNK2 by GSK3β. [Display omitted]
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subjectAkt ; Animals ; Apoptosis ; Apoptosis - drug effects ; Carcinoma, Hepatocellular - pathology ; Cardiac glycosides ; Cardiotonic agents ; Care and treatment ; Cell Line, Tumor ; Cell Proliferation ; Digitalis - chemistry ; Dosage and administration ; ERK ; Health aspects ; Hepatocellular carcinoma ; Humans ; Lanatoside C ; Lanatosides - pharmacology ; Liver cancer ; Liver Neoplasms - pathology ; Medicine, Botanic ; Medicine, Herbal ; Mice ; Mice, Nude ; Oxidative Stress ; PTEN ; PTEN Phosphohydrolase - metabolism ; Signal Transduction ; Xenograft Model Antitumor Assays
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descriptionHepatocellular carcinoma is the second deadliest cancer with limited treatment options. Loss of PTEN causes the P13K/Akt pathway to be hyperactive which contributes to cell survival and resistance to therapeutics in various cancers, including the liver cancer. Hence molecules targeting this pathway present good therapeutic strategies for liver cancer. It was previously reported that Cardiac glycosides possessed antitumor activity by inducing apoptosis of multiple cancer cells through oxidative stress. However, whether Cardiac glycoside Lanatoside C can induce oxidative stress in liver cancer cells and induce cell death both in vitro and in vivo remains unknown. Cell viability was measured by SRB assay. Cell death analysis was investigated by propidium iodide staining with flow cytometry and PARP cleavage. DCFH-DA staining and cytometry were used for intracellular ROS measurement. Protein levels were analyzed by western blot analysis. Antitumor activity was investigated on mice xenografts in vivo. In this study, we found that Cardiac glycosides, particularly Lanatoside C from Digitalis ferruginea could significantly inhibit PTEN protein adequate Huh7 and PTEN deficient Mahlavu human liver cancer cell proliferation by the induction of apoptosis and G2/M arrest in the cells. Lanatoside C was further shown to induce oxidative stress and alter ERK and Akt pathways. Consequently, JNK1 activation resulted in extrinsic apoptotic pathway stimulation in both cells while JNK2 activation involved in the inhibition of cell survival only in PTEN deficient cells. Furthermore, nude mice xenografts followed by MRI showed that Lanatoside C caused a significant decrease in the tumor size. In this study apoptosis induction by Lanatoside C was characterized through ROS altered ERK and Akt pathways in both PTEN adequate epithelial and deficient mesenchymal liver cancer cells. The results indicated that Lanatoside C could be contemplated in liver cancer therapeutics, particularly in PTEN deficient tumors. This is due to Lanatoside C's stress inducing action on ERK and Akt pathways through differential activation of JNK1 and JNK2 by GSK3β. [Display omitted]
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0Akt
1Animals
2Apoptosis
3Apoptosis - drug effects
4Carcinoma, Hepatocellular - pathology
5Cardiac glycosides
6Cardiotonic agents
7Care and treatment
8Cell Line, Tumor
9Cell Proliferation
10Digitalis - chemistry
11Dosage and administration
12ERK
13Health aspects
14Hepatocellular carcinoma
15Humans
16Lanatoside C
17Lanatosides - pharmacology
18Liver cancer
19Liver Neoplasms - pathology
20Medicine, Botanic
21Medicine, Herbal
22Mice
23Mice, Nude
24Oxidative Stress
25PTEN
26PTEN Phosphohydrolase - metabolism
27Signal Transduction
28Xenograft Model Antitumor Assays
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titleLiver cancer cells are sensitive to Lanatoside C induced cell death independent of their PTEN status
authorDurmaz, Irem ; Guven, Ebru Bilget ; Ersahin, Tulin ; Ozturk, Mehmet ; Calis, Ihsan ; Cetin-Atalay, Rengul
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7Care and treatment
8Cell Line, Tumor
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12ERK
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abstractHepatocellular carcinoma is the second deadliest cancer with limited treatment options. Loss of PTEN causes the P13K/Akt pathway to be hyperactive which contributes to cell survival and resistance to therapeutics in various cancers, including the liver cancer. Hence molecules targeting this pathway present good therapeutic strategies for liver cancer. It was previously reported that Cardiac glycosides possessed antitumor activity by inducing apoptosis of multiple cancer cells through oxidative stress. However, whether Cardiac glycoside Lanatoside C can induce oxidative stress in liver cancer cells and induce cell death both in vitro and in vivo remains unknown. Cell viability was measured by SRB assay. Cell death analysis was investigated by propidium iodide staining with flow cytometry and PARP cleavage. DCFH-DA staining and cytometry were used for intracellular ROS measurement. Protein levels were analyzed by western blot analysis. Antitumor activity was investigated on mice xenografts in vivo. In this study, we found that Cardiac glycosides, particularly Lanatoside C from Digitalis ferruginea could significantly inhibit PTEN protein adequate Huh7 and PTEN deficient Mahlavu human liver cancer cell proliferation by the induction of apoptosis and G2/M arrest in the cells. Lanatoside C was further shown to induce oxidative stress and alter ERK and Akt pathways. Consequently, JNK1 activation resulted in extrinsic apoptotic pathway stimulation in both cells while JNK2 activation involved in the inhibition of cell survival only in PTEN deficient cells. Furthermore, nude mice xenografts followed by MRI showed that Lanatoside C caused a significant decrease in the tumor size. In this study apoptosis induction by Lanatoside C was characterized through ROS altered ERK and Akt pathways in both PTEN adequate epithelial and deficient mesenchymal liver cancer cells. The results indicated that Lanatoside C could be contemplated in liver cancer therapeutics, particularly in PTEN deficient tumors. This is due to Lanatoside C's stress inducing action on ERK and Akt pathways through differential activation of JNK1 and JNK2 by GSK3β. [Display omitted]
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