title: Dioscin augments HSV-tk-mediated suicide gene therapy for melanoma by promoting connexin-based intercellular communication.
abstract: Suicide gene therapy is a promising strategy against melanoma. However, the low efficiency of the gene transfer technique can limit its application. Our preliminary data showed that dioscin, a glucoside saponin, could upregulate the expression of connexins Cx26 and Cx43, major components of gap junctions, in melanoma cells. We hypothesized that dioscin may increase the bystander effect of herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) through increasing the formation of gap junctions. Further analysis showed that dioscin indeed could increase the gap junctional intercellular communication in B16 melanoma cells, resulting in more efficient GCV-induced bystander killing in B16tk cells. By contrast, overexpression of dominant negative Cx43 impaired the cell-cell communication of B16 cells and subsequently weakened the bystander effect of HSV-tk/GCV gene therapy. In vivo, combination treatment with dioscin and GCV of tumor-bearing mice with 30% positive B16tk cells and 70% wild-type B16 cells caused a significant reduction in tumor volume and weight compared to treatment with GCV or dioscin alone. Taken together, these results demonstrated that dioscin could augment the bystander effect of the HSV-tk/GCV system through increasing connexin-mediated gap junction coupling.
authors.affiliation: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
authors.forename: Guangxian
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
authors.forename: Yingya
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
authors.forename: Xijuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Pathology, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
authors.forename: Biaoyan
authors.initials: B
authors.lastname: Du
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D024201:Bystander Effect / Q000187:drug effects; D002450:Cell Communication; D002470:Cell Survival / Q000187:drug effects; D000072259:Connexin 26 / Q000378:metabolism; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D017630:Connexins / Q000378:metabolism*; D004144:Diosgenin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D015774:Ganciclovir / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051379:Mice; D009154:Mutation; D018139:Simplexvirus / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D000998:Antiviral Agents; D018031:Connexin 43; D017630:Connexins; D000072259:Connexin 26; C019357:dioscin; D013937:Thymidine Kinase; D004144:Diosgenin; D015774:Ganciclovir
keywords: bystander effect; connexin; dioscin; melanoma; suicide gene