title: Tanshinone IIA increases the bystander effect of herpes simplex virus thymidine kinase/ganciclovir gene therapy via enhanced gap junctional intercellular communication.
abstract: The bystander effect is an intriguing phenomenon by which adjacent cells become sensitized to drug treatment during gene therapy with herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV). This effect is reported to be mediated by gap junctional intercellular communication (GJIC), and therefore, we postulated that upregulation of genes that facilitate GJIC may enhance the HSV-tk/GCV bystander effect. Previous findings have shown Tanshinone IIA (Tan IIA), a chemical substance derived from a Chinese medicine herb, promotes the upregulation of the connexins Cx26 and Cx43 in B16 cells. Because gap junctions are formed by connexins, we hypothesized that Tan IIA might increase GJIC. Our results show that Tan IIA increased GJIC in B16 melanoma cells, leading to more efficient GCV-induced bystander killing in cells stably expressing HSV-tk. Additionally, in vivo experiments demonstrated that tumors in mice with 10% HSV-tk positive B16 cells and 90% wild-type B16 cells became smaller following treatment with the combination of GCV and Tan IIA as compared to GCV or Tan IIA alone. These data demonstrate that Tan IIA can augment the bystander effect of HSV-tk/GCV system through increased gap junction coupling, which adds strength to the promising strategy that develops connexins inducer to potentiate the effects of suicide gene therapy.
authors.affiliation: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, China.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Xiao
authors.forename: Guangxian
authors.initials: G
authors.lastname: Zhang
authors.forename: Pengxiang
authors.initials: P
authors.lastname: Qiu
authors.forename: Xijuan
authors.initials: X
authors.lastname: Liu
authors.forename: Yingya
authors.initials: Y
authors.lastname: Wu
authors.forename: Biaoyan
authors.initials: B
authors.lastname: Du
authors.forename: Jiefen
authors.initials: J
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Tan
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D024201:Bystander Effect / Q000187:drug effects / Q000235:genetics; D000072259:Connexin 26; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005260:Female; D017629:Gap Junctions / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D015398:Signal Transduction; D018139:Simplexvirus / Q000737:chemistry / Q000201:enzymology / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D013937:Thymidine Kinase / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000494:pharmacology*
chemical_list: D045784:Abietanes; D018031:Connexin 43; D017630:Connexins; D004365:Drugs, Chinese Herbal; C000607042:GJB2 protein, human; D014764:Viral Proteins; C021751:tanshinone; D000072259:Connexin 26; D013937:Thymidine Kinase