2. Academic Validation
  3. Augmenting the therapeutic efficacy of adenosine against pancreatic cancer by switching the Akt/p21-dependent senescence to apoptosis

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

  • EBioMedicine. 2019 Sep;47:114-127. doi: 10.1016/j.ebiom.2019.08.068.
Dongqin Yang 1,  Qi Zhang 2,  Yunfang Ma 2,  Zhihui Che 2,  Wenli Zhang 2,  Mengmeng Wu 2,  Lijun Wu 3,  Fuchen Liu 4,  Yiwei Chu 5,  Wei Xu 5,  Mary McGrath 6,  Chunhua Song 6,  Jie Liu 7
Affiliations

Affiliations

  • 1 Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China. Electronic address: kobesakura@fudan.edu.cn.
  • 2 Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.
  • 3 Department of Library, Fudan University, Shanghai, China.
  • 4 The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
  • 5 Department of Immunology of School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 6 Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
  • 7 Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China. Electronic address: jieliu@fudan.edu.cn.
PMID: 31495718 DOI: 10.1016/j.ebiom.2019.08.068
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).

Keywords

Adenosine; Akt-p21 axis; GSK690693; Pancreatic cancer.

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