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Hu C, Chen Z, Zhao W, et al. Vesicular Stomatitis Virus G Glycoprotein and ATRA Enhanced Bystander Killing of Chemoresistant Leukemic Cells by Herpes Simplex Virus Thymidine Kinase/Ganciclovir. Biomol Ther (Seoul). 2014;22(2):114-21doi: 10.4062/biomolther.2013.112.
Hu, C., Chen, Z., Zhao, W., Wei, L., Zheng, Y., He, C., Zeng, Y., & Yin, B. (2014). Vesicular Stomatitis Virus G Glycoprotein and ATRA Enhanced Bystander Killing of Chemoresistant Leukemic Cells by Herpes Simplex Virus Thymidine Kinase/Ganciclovir. Biomolecules & therapeutics, 22(2), 114-21. https://doi.org/10.4062/biomolther.2013.112
Hu, Chenxi, et al. "Vesicular Stomatitis Virus G Glycoprotein and ATRA Enhanced Bystander Killing of Chemoresistant Leukemic Cells by Herpes Simplex Virus Thymidine Kinase/Ganciclovir." Biomolecules & therapeutics vol. 22,2 (2014): 114-21. doi: https://doi.org/10.4062/biomolther.2013.112
Hu C, Chen Z, Zhao W, Wei L, Zheng Y, He C, Zeng Y, Yin B. Vesicular Stomatitis Virus G Glycoprotein and ATRA Enhanced Bystander Killing of Chemoresistant Leukemic Cells by Herpes Simplex Virus Thymidine Kinase/Ganciclovir. Biomol Ther (Seoul). 2014 Feb;22(2):114-21. doi: 10.4062/biomolther.2013.112. PMID: 24753816; PMCID: PMC3975477.
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Biomol Ther (Seoul). 2014 Feb;22(2):114-21. doi: 10.4062/biomolther.2013.112.

Vesicular Stomatitis Virus G Glycoprotein and ATRA Enhanced Bystander Killing of Chemoresistant Leukemic Cells by Herpes Simplex Virus Thymidine Kinase/Ganciclovir.

Biomolecules & therapeutics

Chenxi Hu, Zheng Chen, Wenjun Zhao, Lirong Wei, Yanwen Zheng, Chao He, Yan Zeng, Bin Yin

Affiliations

  1. Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu province, 215123, PR China.
  2. Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.
  3. Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu province, 215123, PR China ; Thrombosis and Hemostasis Key Lab of the Ministry of Health, Soochow University, Suzhou, Jiangsu Province, 215006, PR China.

PMID: 24753816 PMCID: PMC3975477 DOI: 10.4062/biomolther.2013.112

Abstract

Refractoriness of acute myeloid leukemia (AML) cells to chemotherapeutics represents a major clinical barrier. Suicide gene therapy for cancer has been attractive but with limited clinical efficacy. In this study, we investigated the potential application of herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) based system to inhibit chemoresistant AML cells. We first generated Ara-C resistant K562 cells and doxorubicin-resistant THP-1 cells. We found that the HSV-TK/GCV anticancer system suppressed drug resistant leukemic cells in culture. Chemoresistant AML cell lines displayed similar sensitivity to HSV-TK/GCV. Moreover, HSV-TK/GCV killing of leukemic cells was augmented to a mild but significant extent by all-trans retinoic acid (ATRA) with concomitant upregulation of Connexin 43, a major component of gap junctions. Interestingly, HSV-TK/GCV killing was enhanced by expression of vesicular stomatitis virus G glycoprotein (VSV-G), a fusogenic membrane protein, which also increased leukemic cell fusion. Co-culture resistant cells expressing HSV-TK and cells stably transduced with VSV-G showed that expression of VSV-G could promote the bystander killing effect of HSV-TK/GCV. Furthermore, combination of HSV-TK/GCV with VSV-G plus ATRA produced more pronounced antileukemia effect. These results suggest that the HSV-TK/GCV system in combination with fusogenic membrane proteins and/or ATRA could provide a strategy to mitigate the chemoresistance of AML.

Keywords: ATRA; Bystander killing; Chemoresisitant leukemia cells; HSV-TK/GCV; VSV-G

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