title: Tanshinone IIA enhances bystander cell killing of cancer cells expressing Drosophila melanogaster deoxyribonucleoside kinase in nuclei and mitochondria.
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.
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, P.R. China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Center of Experiment Technology and Medical Research, China Medical University, Shenyang, Liaoning, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, P.R. China.
authors.forename: Xiaoshen
authors.initials: X
authors.lastname: Dong
authors.affiliation: Laboratory 1, Cancer Institute, China Medical University, Shenyang, Liaoning, P.R. China.
authors.forename: Anning
authors.initials: A
authors.lastname: He
authors.affiliation: Brandeis University, Waltham, MA, USA.
authors.forename: Caiwei
authors.initials: C
authors.lastname: Zheng
authors.affiliation: Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Johansson
authors.affiliation: Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, P.R. China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Zheng
mesh_terms: D045784:Abietanes / Q000008:administration & dosage*; D000818:Animals; D024201:Bystander Effect; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000072259:Connexin 26; D017630:Connexins; D003857:Deoxyuridine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004331:Drosophila melanogaster / Q000201:enzymology / Q000235:genetics; D005690:Galactose / Q000008:administration & dosage / Q000031:analogs & derivatives; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics; D019913:Nuclear Localization Signals / Q000235:genetics; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D013941:Thymine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: C460040:1-galactopyranosylthymine; D045784:Abietanes; D017630:Connexins; C000607042:GJB2 protein, human; D019913:Nuclear Localization Signals; C021751:tanshinone; D000072259:Connexin 26; D017853:Phosphotransferases (Alcohol Group Acceptor); C020018:deoxyribonucleoside kinases; D013941:Thymine; D003857:Deoxyuridine; D005690:Galactose