Augmenting the therapeutic efficacy of adenosine against pancreatic cancer by switching the Akt/p21-dependent senescence to apoptosis

Dongqin Yang, Qi Zhang, Yunfang Ma, Zhihui Che, Wenli Zhang, Mengmeng Wu, Lijun Wu, Fuchen Liu, Yiwei Chu, Wei Xu, Mary McGrath, Chunhua Song, Jie Liu

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: There are many reports of the anti-tumour effects of exogenous adenosine in gastrointestinal tumours. Gemcitabine, a first line agent for patients with poor performance status, and adenosine have structural similarities. For these reasons, it is worth exploring the therapeutic efficacy of adenosine and its underlying mechanism in pancreatic cancer. Methods: Tumour volumes and survival periods were measured in a patient-derived xenograft (PDX) model of pancreatic cancer. The Akt-p21 signalling axis was blocked by p21 silencing or by the Akt inhibitor GSK690693. The combined effect of GSK690693 and adenosine was calculated by the Chou-Talalay equation and verified by measuring fluorescent areas in orthotopic models. Findings: Among the PDX mice, the tumour volume in the adenosine treatment group was only 61% of that in the saline treatment group. Adenosine treatment in combination with the Akt inhibitor, GSK690693, or the silencing of p21 to interfere with the Akt-p21 axis can switch the senescence-to-apoptosis signal and alleviate drug resistance. A GSK690693-adenosine combination caused 37.4% further reduction of tumour fluorescent areas in orthotopic models compared with that observed in adenosine monotherapy. Interpretation: Our data confirmed the therapeutic effect of adenosine on pancreatic cancer, and revealed the potential of Akt inhibitors as sensitization agents in this treatment. Fund: The work is supported by grants from the National Natural Science Foundation of China to Dongqin Yang ( 81572336, 81770579) and Jie Liu ( 81630016, 81830080), and jointly by the Development Fund for Shanghai Talents ( 201660).

Original languageEnglish (US)
Pages (from-to)114-127
Number of pages14
JournalEBioMedicine
Volume47
DOIs
StatePublished - Sep 1 2019

Fingerprint

Pancreatic Neoplasms
Adenosine
Apoptosis
Tumors
Therapeutics
gemcitabine
Tumor Burden
Heterografts
Natural Science Disciplines
Natural sciences
Neoplasms
Aptitude
Organized Financing
Proxy
Therapeutic Uses
Drug Resistance
China
Switches
Survival
GSK690693

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yang, Dongqin ; Zhang, Qi ; Ma, Yunfang ; Che, Zhihui ; Zhang, Wenli ; Wu, Mengmeng ; Wu, Lijun ; Liu, Fuchen ; Chu, Yiwei ; Xu, Wei ; McGrath, Mary ; Song, Chunhua ; Liu, Jie. / Augmenting the therapeutic efficacy of adenosine against pancreatic cancer by switching the Akt/p21-dependent senescence to apoptosis. In: EBioMedicine. 2019 ; Vol. 47. pp. 114-127.
@article{757cec18e3d34c40aaa54a22ed49e938,
title = "Augmenting the therapeutic efficacy of adenosine against pancreatic cancer by switching the Akt/p21-dependent senescence to apoptosis",
abstract = "Background: There are many reports of the anti-tumour effects of exogenous adenosine in gastrointestinal tumours. Gemcitabine, a first line agent for patients with poor performance status, and adenosine have structural similarities. For these reasons, it is worth exploring the therapeutic efficacy of adenosine and its underlying mechanism in pancreatic cancer. Methods: Tumour volumes and survival periods were measured in a patient-derived xenograft (PDX) model of pancreatic cancer. The Akt-p21 signalling axis was blocked by p21 silencing or by the Akt inhibitor GSK690693. The combined effect of GSK690693 and adenosine was calculated by the Chou-Talalay equation and verified by measuring fluorescent areas in orthotopic models. Findings: Among the PDX mice, the tumour volume in the adenosine treatment group was only 61{\%} of that in the saline treatment group. Adenosine treatment in combination with the Akt inhibitor, GSK690693, or the silencing of p21 to interfere with the Akt-p21 axis can switch the senescence-to-apoptosis signal and alleviate drug resistance. A GSK690693-adenosine combination caused 37.4{\%} further reduction of tumour fluorescent areas in orthotopic models compared with that observed in adenosine monotherapy. Interpretation: Our data confirmed the therapeutic effect of adenosine on pancreatic cancer, and revealed the potential of Akt inhibitors as sensitization agents in this treatment. Fund: The work is supported by grants from the National Natural Science Foundation of China to Dongqin Yang ( 81572336, 81770579) and Jie Liu ( 81630016, 81830080), and jointly by the Development Fund for Shanghai Talents ( 201660).",
author = "Dongqin Yang and Qi Zhang and Yunfang Ma and Zhihui Che and Wenli Zhang and Mengmeng Wu and Lijun Wu and Fuchen Liu and Yiwei Chu and Wei Xu and Mary McGrath and Chunhua Song and Jie Liu",
year = "2019",
month = "9",
day = "1",
doi = "10.1016/j.ebiom.2019.08.068",
language = "English (US)",
volume = "47",
pages = "114--127",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",

}

Yang, D, Zhang, Q, Ma, Y, Che, Z, Zhang, W, Wu, M, Wu, L, Liu, F, Chu, Y, Xu, W, McGrath, M, Song, C & Liu, J 2019, 'Augmenting the therapeutic efficacy of adenosine against pancreatic cancer by switching the Akt/p21-dependent senescence to apoptosis', EBioMedicine, vol. 47, pp. 114-127. https://doi.org/10.1016/j.ebiom.2019.08.068

Augmenting the therapeutic efficacy of adenosine against pancreatic cancer by switching the Akt/p21-dependent senescence to apoptosis. / Yang, Dongqin; Zhang, Qi; Ma, Yunfang; Che, Zhihui; Zhang, Wenli; Wu, Mengmeng; Wu, Lijun; Liu, Fuchen; Chu, Yiwei; Xu, Wei; McGrath, Mary; Song, Chunhua; Liu, Jie.

In: EBioMedicine, Vol. 47, 01.09.2019, p. 114-127.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Augmenting the therapeutic efficacy of adenosine against pancreatic cancer by switching the Akt/p21-dependent senescence to apoptosis

AU - Yang, Dongqin

AU - Zhang, Qi

AU - Ma, Yunfang

AU - Che, Zhihui

AU - Zhang, Wenli

AU - Wu, Mengmeng

AU - Wu, Lijun

AU - Liu, Fuchen

AU - Chu, Yiwei

AU - Xu, Wei

AU - McGrath, Mary

AU - Song, Chunhua

AU - Liu, Jie

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Background: There are many reports of the anti-tumour effects of exogenous adenosine in gastrointestinal tumours. Gemcitabine, a first line agent for patients with poor performance status, and adenosine have structural similarities. For these reasons, it is worth exploring the therapeutic efficacy of adenosine and its underlying mechanism in pancreatic cancer. Methods: Tumour volumes and survival periods were measured in a patient-derived xenograft (PDX) model of pancreatic cancer. The Akt-p21 signalling axis was blocked by p21 silencing or by the Akt inhibitor GSK690693. The combined effect of GSK690693 and adenosine was calculated by the Chou-Talalay equation and verified by measuring fluorescent areas in orthotopic models. Findings: Among the PDX mice, the tumour volume in the adenosine treatment group was only 61% of that in the saline treatment group. Adenosine treatment in combination with the Akt inhibitor, GSK690693, or the silencing of p21 to interfere with the Akt-p21 axis can switch the senescence-to-apoptosis signal and alleviate drug resistance. A GSK690693-adenosine combination caused 37.4% further reduction of tumour fluorescent areas in orthotopic models compared with that observed in adenosine monotherapy. Interpretation: Our data confirmed the therapeutic effect of adenosine on pancreatic cancer, and revealed the potential of Akt inhibitors as sensitization agents in this treatment. Fund: The work is supported by grants from the National Natural Science Foundation of China to Dongqin Yang ( 81572336, 81770579) and Jie Liu ( 81630016, 81830080), and jointly by the Development Fund for Shanghai Talents ( 201660).

AB - Background: There are many reports of the anti-tumour effects of exogenous adenosine in gastrointestinal tumours. Gemcitabine, a first line agent for patients with poor performance status, and adenosine have structural similarities. For these reasons, it is worth exploring the therapeutic efficacy of adenosine and its underlying mechanism in pancreatic cancer. Methods: Tumour volumes and survival periods were measured in a patient-derived xenograft (PDX) model of pancreatic cancer. The Akt-p21 signalling axis was blocked by p21 silencing or by the Akt inhibitor GSK690693. The combined effect of GSK690693 and adenosine was calculated by the Chou-Talalay equation and verified by measuring fluorescent areas in orthotopic models. Findings: Among the PDX mice, the tumour volume in the adenosine treatment group was only 61% of that in the saline treatment group. Adenosine treatment in combination with the Akt inhibitor, GSK690693, or the silencing of p21 to interfere with the Akt-p21 axis can switch the senescence-to-apoptosis signal and alleviate drug resistance. A GSK690693-adenosine combination caused 37.4% further reduction of tumour fluorescent areas in orthotopic models compared with that observed in adenosine monotherapy. Interpretation: Our data confirmed the therapeutic effect of adenosine on pancreatic cancer, and revealed the potential of Akt inhibitors as sensitization agents in this treatment. Fund: The work is supported by grants from the National Natural Science Foundation of China to Dongqin Yang ( 81572336, 81770579) and Jie Liu ( 81630016, 81830080), and jointly by the Development Fund for Shanghai Talents ( 201660).

UR - http://www.scopus.com/inward/record.url?scp=85071694015&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071694015&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2019.08.068

DO - 10.1016/j.ebiom.2019.08.068

M3 - Article

C2 - 31495718

AN - SCOPUS:85071694015

VL - 47

SP - 114

EP - 127

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -