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The identification of the ATR inhibitor VE-822 as a therapeutic strategy for enhancing cisplatin chemosensitivity in esophageal squamous cell carcinoma

Inducing DNA damage is known to be one of the mechanisms of cytotoxic chemotherapy agents for cancer such as cisplatin. The endogenous DNA damage response confers chemoresistance to these agents by repairing DNA damage. The initiation and transduction of the DNA damage response (DDR) signaling pathw... Full description

Journal Title: Cancer letters 2018-09-28, Vol.432, p.56-68
Main Author: Shi, Qi
Other Authors: Shen, Lu-Yan , Dong, Bin , Fu, Hao , Kang, Xiao-Zheng , Yang, Yong-Bo , Dai, Liang , Yan, Wan-Pu , Xiong, Hong-Chao , Liang, Zhen , Chen, Ke-Neng
Format: Electronic Article Electronic Article
Language: English
Subjects:
DNA
Quelle: Alma/SFX Local Collection
Publisher: Ireland: Elsevier B.V
ID: ISSN: 0304-3835
Link: https://www.ncbi.nlm.nih.gov/pubmed/29890208
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title: The identification of the ATR inhibitor VE-822 as a therapeutic strategy for enhancing cisplatin chemosensitivity in esophageal squamous cell carcinoma
format: Article
creator:
  • Shi, Qi
  • Shen, Lu-Yan
  • Dong, Bin
  • Fu, Hao
  • Kang, Xiao-Zheng
  • Yang, Yong-Bo
  • Dai, Liang
  • Yan, Wan-Pu
  • Xiong, Hong-Chao
  • Liang, Zhen
  • Chen, Ke-Neng
subjects:
  • Activation
  • Adjuvant treatment
  • Animals
  • Antigens
  • Antimitotic agents
  • Antineoplastic agents
  • Antineoplastic Agents - pharmacology
  • Apoptosis
  • Ataxia
  • Ataxia telangiectasia
  • Ataxia telangiectasia mutated protein
  • Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors
  • Ataxia Telangiectasia Mutated Proteins - genetics
  • Ataxia Telangiectasia Mutated Proteins - metabolism
  • ATM deficiency
  • ATR inhibitor
  • Cancer
  • Cancer therapies
  • Carcinoma, Squamous Cell - drug therapy
  • Carcinoma, Squamous Cell - metabolism
  • Carcinoma, Squamous Cell - pathology
  • Cell Cycle
  • Cell Proliferation
  • Cell survival
  • Chemoresistance
  • Chemotherapy
  • CHK1 protein
  • Cisplatin
  • Cisplatin - pharmacology
  • CRISPR-Cas Systems
  • Cytotoxicity
  • Damage
  • Deoxyribonucleic acid
  • DNA
  • DNA damage
  • DNA damage response
  • DNA repair
  • Drug dosages
  • Drug Resistance, Neoplasm - drug effects
  • Esophageal cancer
  • Esophageal Neoplasms - drug therapy
  • Esophageal Neoplasms - metabolism
  • Esophageal Neoplasms - pathology
  • Esophagus
  • Female
  • G1 phase
  • Gene Expression Regulation, Neoplastic
  • Glycoproteins
  • Health aspects
  • Humans
  • Inhibition
  • Isoxazoles - pharmacology
  • Kinases
  • Maintenance
  • Medical prognosis
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Prognosis
  • Pyrazines - pharmacology
  • Sensitizing
  • Signal Transduction
  • Squamous cell carcinoma
  • Strategy
  • Studies
  • Surgery
  • Survival
  • Survival Rate
  • Synergistic effect
  • Thoracic surgery
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
ispartof: Cancer letters, 2018-09-28, Vol.432, p.56-68
description: Inducing DNA damage is known to be one of the mechanisms of cytotoxic chemotherapy agents for cancer such as cisplatin. The endogenous DNA damage response confers chemoresistance to these agents by repairing DNA damage. The initiation and transduction of the DNA damage response (DDR) signaling pathway, which is dependent on the activation of ATM (ataxia-telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3-related), is essential for DNA damage repair, the maintenance of genomic stability and cell survival. Therefore, ATM or ATR inhibition is considered as a promising strategy for sensitizing cancer cells to chemotherapy. This study is aimed to explore the effect of ATR inhibitor on sensitizing ESCC (esophageal squamous cell carcinoma) cells to cisplatin, and whether ATM deficiency could impact the sensitization. We found that 21.5% of ESCC cases had ATM deficiency and that patients with ATR activation after neoadjuvant chemotherapy had worse chemotherapy response and poorer overall survival than that without ATR activation (32 mons vs. >140mons). Then, it was shown that VE-822 inhibited ATR-CHK1 pathway activation, leading to the accumulation of cisplatin-modified DNA. And it inhibited cell proliferation, induced cell cycle arrest in G1 phase and enhanced cell apoptosis. Moreover, VE-822 significantly sensitized ESCC cells to cisplatin, and these two drugs had synergistic effects, especially in ATM-deficient cells, in vitro and in vivo. Our results suggest that ATR inhibition combining with cisplatin is a new strategy for managing patients with ESCC, especially those with ATM-deficiency. However, this is an idea that requires further validation. •ATR activation was associated with efficiency of neoadjuvant chemotherapy.•VE-822 promoted cell apoptosis and induced cell cycle arrest in ESCC cells.•VE-822 sensitized ESCC cells to cisplatin, in vitro and in vivo.•VE-822 along with cisplatin induces DNA-cisplatin adduct accumulation.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0304-3835
fulltext: fulltext
issn:
  • 0304-3835
  • 1872-7980
url: Link


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titleThe identification of the ATR inhibitor VE-822 as a therapeutic strategy for enhancing cisplatin chemosensitivity in esophageal squamous cell carcinoma
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creatorShi, Qi ; Shen, Lu-Yan ; Dong, Bin ; Fu, Hao ; Kang, Xiao-Zheng ; Yang, Yong-Bo ; Dai, Liang ; Yan, Wan-Pu ; Xiong, Hong-Chao ; Liang, Zhen ; Chen, Ke-Neng
creatorcontribShi, Qi ; Shen, Lu-Yan ; Dong, Bin ; Fu, Hao ; Kang, Xiao-Zheng ; Yang, Yong-Bo ; Dai, Liang ; Yan, Wan-Pu ; Xiong, Hong-Chao ; Liang, Zhen ; Chen, Ke-Neng
descriptionInducing DNA damage is known to be one of the mechanisms of cytotoxic chemotherapy agents for cancer such as cisplatin. The endogenous DNA damage response confers chemoresistance to these agents by repairing DNA damage. The initiation and transduction of the DNA damage response (DDR) signaling pathway, which is dependent on the activation of ATM (ataxia-telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3-related), is essential for DNA damage repair, the maintenance of genomic stability and cell survival. Therefore, ATM or ATR inhibition is considered as a promising strategy for sensitizing cancer cells to chemotherapy. This study is aimed to explore the effect of ATR inhibitor on sensitizing ESCC (esophageal squamous cell carcinoma) cells to cisplatin, and whether ATM deficiency could impact the sensitization. We found that 21.5% of ESCC cases had ATM deficiency and that patients with ATR activation after neoadjuvant chemotherapy had worse chemotherapy response and poorer overall survival than that without ATR activation (32 mons vs. >140mons). Then, it was shown that VE-822 inhibited ATR-CHK1 pathway activation, leading to the accumulation of cisplatin-modified DNA. And it inhibited cell proliferation, induced cell cycle arrest in G1 phase and enhanced cell apoptosis. Moreover, VE-822 significantly sensitized ESCC cells to cisplatin, and these two drugs had synergistic effects, especially in ATM-deficient cells, in vitro and in vivo. Our results suggest that ATR inhibition combining with cisplatin is a new strategy for managing patients with ESCC, especially those with ATM-deficiency. However, this is an idea that requires further validation. •ATR activation was associated with efficiency of neoadjuvant chemotherapy.•VE-822 promoted cell apoptosis and induced cell cycle arrest in ESCC cells.•VE-822 sensitized ESCC cells to cisplatin, in vitro and in vivo.•VE-822 along with cisplatin induces DNA-cisplatin adduct accumulation.
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languageeng
publisherIreland: Elsevier B.V
subjectActivation ; Adjuvant treatment ; Animals ; Antigens ; Antimitotic agents ; Antineoplastic agents ; Antineoplastic Agents - pharmacology ; Apoptosis ; Ataxia ; Ataxia telangiectasia ; Ataxia telangiectasia mutated protein ; Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors ; Ataxia Telangiectasia Mutated Proteins - genetics ; Ataxia Telangiectasia Mutated Proteins - metabolism ; ATM deficiency ; ATR inhibitor ; Cancer ; Cancer therapies ; Carcinoma, Squamous Cell - drug therapy ; Carcinoma, Squamous Cell - metabolism ; Carcinoma, Squamous Cell - pathology ; Cell Cycle ; Cell Proliferation ; Cell survival ; Chemoresistance ; Chemotherapy ; CHK1 protein ; Cisplatin ; Cisplatin - pharmacology ; CRISPR-Cas Systems ; Cytotoxicity ; Damage ; Deoxyribonucleic acid ; DNA ; DNA damage ; DNA damage response ; DNA repair ; Drug dosages ; Drug Resistance, Neoplasm - drug effects ; Esophageal cancer ; Esophageal Neoplasms - drug therapy ; Esophageal Neoplasms - metabolism ; Esophageal Neoplasms - pathology ; Esophagus ; Female ; G1 phase ; Gene Expression Regulation, Neoplastic ; Glycoproteins ; Health aspects ; Humans ; Inhibition ; Isoxazoles - pharmacology ; Kinases ; Maintenance ; Medical prognosis ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Prognosis ; Pyrazines - pharmacology ; Sensitizing ; Signal Transduction ; Squamous cell carcinoma ; Strategy ; Studies ; Surgery ; Survival ; Survival Rate ; Synergistic effect ; Thoracic surgery ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
ispartofCancer letters, 2018-09-28, Vol.432, p.56-68
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8Xiong, Hong-Chao
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0The identification of the ATR inhibitor VE-822 as a therapeutic strategy for enhancing cisplatin chemosensitivity in esophageal squamous cell carcinoma
1Cancer letters
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descriptionInducing DNA damage is known to be one of the mechanisms of cytotoxic chemotherapy agents for cancer such as cisplatin. The endogenous DNA damage response confers chemoresistance to these agents by repairing DNA damage. The initiation and transduction of the DNA damage response (DDR) signaling pathway, which is dependent on the activation of ATM (ataxia-telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3-related), is essential for DNA damage repair, the maintenance of genomic stability and cell survival. Therefore, ATM or ATR inhibition is considered as a promising strategy for sensitizing cancer cells to chemotherapy. This study is aimed to explore the effect of ATR inhibitor on sensitizing ESCC (esophageal squamous cell carcinoma) cells to cisplatin, and whether ATM deficiency could impact the sensitization. We found that 21.5% of ESCC cases had ATM deficiency and that patients with ATR activation after neoadjuvant chemotherapy had worse chemotherapy response and poorer overall survival than that without ATR activation (32 mons vs. >140mons). Then, it was shown that VE-822 inhibited ATR-CHK1 pathway activation, leading to the accumulation of cisplatin-modified DNA. And it inhibited cell proliferation, induced cell cycle arrest in G1 phase and enhanced cell apoptosis. Moreover, VE-822 significantly sensitized ESCC cells to cisplatin, and these two drugs had synergistic effects, especially in ATM-deficient cells, in vitro and in vivo. Our results suggest that ATR inhibition combining with cisplatin is a new strategy for managing patients with ESCC, especially those with ATM-deficiency. However, this is an idea that requires further validation. •ATR activation was associated with efficiency of neoadjuvant chemotherapy.•VE-822 promoted cell apoptosis and induced cell cycle arrest in ESCC cells.•VE-822 sensitized ESCC cells to cisplatin, in vitro and in vivo.•VE-822 along with cisplatin induces DNA-cisplatin adduct accumulation.
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0Activation
1Adjuvant treatment
2Animals
3Antigens
4Antimitotic agents
5Antineoplastic agents
6Antineoplastic Agents - pharmacology
7Apoptosis
8Ataxia
9Ataxia telangiectasia
10Ataxia telangiectasia mutated protein
11Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors
12Ataxia Telangiectasia Mutated Proteins - genetics
13Ataxia Telangiectasia Mutated Proteins - metabolism
14ATM deficiency
15ATR inhibitor
16Cancer
17Cancer therapies
18Carcinoma, Squamous Cell - drug therapy
19Carcinoma, Squamous Cell - metabolism
20Carcinoma, Squamous Cell - pathology
21Cell Cycle
22Cell Proliferation
23Cell survival
24Chemoresistance
25Chemotherapy
26CHK1 protein
27Cisplatin
28Cisplatin - pharmacology
29CRISPR-Cas Systems
30Cytotoxicity
31Damage
32Deoxyribonucleic acid
33DNA
34DNA damage
35DNA damage response
36DNA repair
37Drug dosages
38Drug Resistance, Neoplasm - drug effects
39Esophageal cancer
40Esophageal Neoplasms - drug therapy
41Esophageal Neoplasms - metabolism
42Esophageal Neoplasms - pathology
43Esophagus
44Female
45G1 phase
46Gene Expression Regulation, Neoplastic
47Glycoproteins
48Health aspects
49Humans
50Inhibition
51Isoxazoles - pharmacology
52Kinases
53Maintenance
54Medical prognosis
55Mice
56Mice, Inbred BALB C
57Mice, Nude
58Prognosis
59Pyrazines - pharmacology
60Sensitizing
61Signal Transduction
62Squamous cell carcinoma
63Strategy
64Studies
65Surgery
66Survival
67Survival Rate
68Synergistic effect
69Thoracic surgery
70Tumor Cells, Cultured
71Xenograft Model Antitumor Assays
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titleThe identification of the ATR inhibitor VE-822 as a therapeutic strategy for enhancing cisplatin chemosensitivity in esophageal squamous cell carcinoma
authorShi, Qi ; Shen, Lu-Yan ; Dong, Bin ; Fu, Hao ; Kang, Xiao-Zheng ; Yang, Yong-Bo ; Dai, Liang ; Yan, Wan-Pu ; Xiong, Hong-Chao ; Liang, Zhen ; Chen, Ke-Neng
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1Adjuvant treatment
2Animals
3Antigens
4Antimitotic agents
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6Antineoplastic Agents - pharmacology
7Apoptosis
8Ataxia
9Ataxia telangiectasia
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16Cancer
17Cancer therapies
18Carcinoma, Squamous Cell - drug therapy
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21Cell Cycle
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29CRISPR-Cas Systems
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52Kinases
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54Medical prognosis
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60Sensitizing
61Signal Transduction
62Squamous cell carcinoma
63Strategy
64Studies
65Surgery
66Survival
67Survival Rate
68Synergistic effect
69Thoracic surgery
70Tumor Cells, Cultured
71Xenograft Model Antitumor Assays
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abstractInducing DNA damage is known to be one of the mechanisms of cytotoxic chemotherapy agents for cancer such as cisplatin. The endogenous DNA damage response confers chemoresistance to these agents by repairing DNA damage. The initiation and transduction of the DNA damage response (DDR) signaling pathway, which is dependent on the activation of ATM (ataxia-telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3-related), is essential for DNA damage repair, the maintenance of genomic stability and cell survival. Therefore, ATM or ATR inhibition is considered as a promising strategy for sensitizing cancer cells to chemotherapy. This study is aimed to explore the effect of ATR inhibitor on sensitizing ESCC (esophageal squamous cell carcinoma) cells to cisplatin, and whether ATM deficiency could impact the sensitization. We found that 21.5% of ESCC cases had ATM deficiency and that patients with ATR activation after neoadjuvant chemotherapy had worse chemotherapy response and poorer overall survival than that without ATR activation (32 mons vs. >140mons). Then, it was shown that VE-822 inhibited ATR-CHK1 pathway activation, leading to the accumulation of cisplatin-modified DNA. And it inhibited cell proliferation, induced cell cycle arrest in G1 phase and enhanced cell apoptosis. Moreover, VE-822 significantly sensitized ESCC cells to cisplatin, and these two drugs had synergistic effects, especially in ATM-deficient cells, in vitro and in vivo. Our results suggest that ATR inhibition combining with cisplatin is a new strategy for managing patients with ESCC, especially those with ATM-deficiency. However, this is an idea that requires further validation. •ATR activation was associated with efficiency of neoadjuvant chemotherapy.•VE-822 promoted cell apoptosis and induced cell cycle arrest in ESCC cells.•VE-822 sensitized ESCC cells to cisplatin, in vitro and in vivo.•VE-822 along with cisplatin induces DNA-cisplatin adduct accumulation.
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pmid29890208
doi10.1016/j.canlet.2018.06.010
orcididhttps://orcid.org/0000-0002-0757-7094