Synergistic antitumor effects of CDK inhibitor SNS‑032 and an oncolytic adenovirus co‑expressing TRAIL and Smac in pancreatic cancer

Ge,Yun; Lei,Wen; Ma,Yingyu; Wang,Yigang; Wei,Buyun; Chen,Xiaoyi; Ru,Guoqing; He,Xianglei; Mou,Xiaozhou; Wang,Shibing

doi:10.3892/mmr.2017.6472

Synergistic antitumor effects of CDK inhibitor SNS‑032 and an oncolytic adenovirus co‑expressing TRAIL and Smac in pancreatic cancer

Authors:
- Yun Ge
- Wen Lei
- Yingyu Ma
- Yigang Wang
- Buyun Wei
- Xiaoyi Chen
- Guoqing Ru
- Xianglei He
- Xiaozhou Mou
- Shibing Wang
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Affiliations: Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences, Zhejiang Sci‑Tech University, Hangzhou, Zhejiang 310018, P.R. China, Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China, Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China, Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
Published online on: April 12, 2017 https://doi.org/10.3892/mmr.2017.6472
Pages: 3521-3528
Copyright: © Ge et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Gene therapy using oncolytic adenoviruses is a novel approach for human cancer therapeutics. The current study aimed to investigate whether the combined use of an adenovirus expressing tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL) and second mitochondria‑derived activator of caspase (Smac) upon caspase activation (ZD55‑TRAIL‑IETD‑Smac) and cyclin‑dependent kinase (CDK) inhibitor SNS‑032 will synergistically reinforce their anti‑pancreatic cancer activities. The experiments in vitro demonstrated that SNS‑032 enhances ZD55‑TRAIL‑IETD‑Smac‑induced apoptosis and causes marked pancreatic cancer cell death. Western blot assays suggested that the SNS‑032 intensified ZD55‑TRAIL‑IETD‑Smac‑induced apoptosis of pancreatic cancer cells by affecting anti‑apoptotic signaling elements, including CDK‑2, CDK‑9, Mcl‑1 and XIAP. Additionally, animal experiments further confirmed that the combination of SNS‑032 and ZD55‑TRAIL‑IETD‑Smac significantly inhibited the growth of BxPC‑3 pancreatic tumor xenografts. In conclusion, the present study demonstrated that SNS‑032 sensitizes human pancreatic cancer cells to ZD55‑TRAIL‑IETD‑Smac‑induced cell death in vitro and in vivo. These findings indicate that combined treatment with SNS‑032 and ZD55‑TRAIL‑IETD‑Smac could represent a rational approach for anti‑pancreatic cancer therapy.

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