Tanshinone IIA enhances bystander cell killing of cancer cells expressing Drosophila melanogaster deoxyribonucleoside kinase in nuclei and mitochondria

Jiang,Haiyang; Zhao,Lei; Dong,Xiaoshen; He,Anning; Zheng,Caiwei; Johansson,Magnus; Karlsson,Anna; Zheng,Xinyu

doi:10.3892/or.2015.4102

Tanshinone IIA enhances bystander cell killing of cancer cells expressing Drosophila melanogaster deoxyribonucleoside kinase in nuclei and mitochondria

Authors:
- Haiyang Jiang
- Lei Zhao
- Xiaoshen Dong
- Anning He
- Caiwei Zheng
- Magnus Johansson
- Anna Karlsson
- Xinyu Zheng
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Affiliations: Department of Breast Surgery, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, P.R. China, Center of Experiment Technology and Medical Research, China Medical University, Shenyang, Liaoning, P.R. China, Laboratory 1, Cancer Institute, China Medical University, Shenyang, Liaoning, P.R. China, Brandeis University, Waltham, MA, USA, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
Published online on: July 2, 2015 https://doi.org/10.3892/or.2015.4102
Pages: 1487-1493

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Abstract

Heterologous expression of the Drosophila melanogaster multi-substrate deoxyribonucleoside kinase (Dm-dNK) increases the sensitivity of cancer cells to several cytotoxic nucleoside analogs. Thus, it may be used as a suicide gene in combined gene/chemotherapy treatment of cancer. To further characterize this potential suicide gene, we constructed two retroviral vectors that enabled the expression of Dm-dNK in cancer cells. One vector harbored the wild‑type enzyme that localized to the nucleus. The other vector harbored a mitochondrial localized mutant enzyme that was constructed by deleting the nuclear localization signal and fusing it to a mitochondrial import signal of cytochrome c oxidase. A thymidine kinase-deficient osteosarcoma cell line was transduced with the recombinant viruses. The sensitivity and bystander cell killing in the presence of pyrimidine nucleoside analogs (E)-5-(2-bromovinyl)‑2'‑deoxyuridine and 1-β-D-arabinofuranosylthymine were investigated. Tanshinone IIA is a constituent of Danshen; a traditional Chinese medicine used in the treatment of cardiovascular diseases. This study also looked at the influence of Tanshinone IIA on the bystander effect and the underlying mechanisms. We showed that sensitivity of the osteosarcoma cell line to the nucleoside analogs and the efficiency of bystander cell killing were independent of the subcellular localization of Dm-dNK. The enhanced effect of tanshinone IIA on the bystander effect was related to the increased expression of Cx43 and Cx26.

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