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
N1 - Publisher Copyright:
© 2019
PY - 2019/9
Y1 - 2019/9
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).
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U2 - 10.1016/j.ebiom.2019.08.068
DO - 10.1016/j.ebiom.2019.08.068
M3 - Article
C2 - 31495718
AN - SCOPUS:85071694015
SN - 2352-3964
VL - 47
SP - 114
EP - 127
JO - EBioMedicine
JF - EBioMedicine
ER -
