Dioscin augments HSV-tk-mediated suicide gene therapy for melanoma by promoting connexin-based intercellular communication.

Jianyong Xiao,Biaoyan Du,Yuhui Tan,Guangxian Zhang,Bin Li,Yingya Wu,Xijuan Liu

doi:10.18632/oncotarget.13655

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.

Highlights

Melanoma is a malignant skin cancer, which has drawn much concern for its high mortality rate and increased incidence in recent decades [1]
To test the effect of dioscin on gap junctional intercellular communication (GJIC) of B16 cells, we first performed the MTT assay to determine the applicable concentration of dioscin
Cx26 was highly expressed in B16 cells under dioscin treatment (4 μM), indicating that exposure of these cells to dioscin could upregulate the expression of connexins (Figure 2A)

Summary

Introduction

Melanoma is a malignant skin cancer, which has drawn much concern for its high mortality rate and increased incidence in recent decades [1]. Due to the chemoresistance and rapid metastasis of melanoma tumors, conventional treatments by surgical removal, chemotherapy and radiotherapy have provided unsatisfactory outcomes for patients. Targeted gene therapy currently is recommended for patients with melanoma. Clinical trials have demonstrated the feasibility and safety of gene therapy against malignant melanoma [2]. The goal of gene therapy targeted to melanoma cells is to transfer tumor suppressor genes or to inactivate aberrant oncogene expression. The major limitation of gene therapy is the efficiency of gene transfer

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Results

Conclusion