Vesicular Stomatitis Virus G Glycoprotein and ATRA Enhanced Bystander Killing of Chemoresistant Leukemic Cells by Herpes Simplex Virus Thymidine Kinase/Ganciclovir.
- Author:
Chenxi HU
1
;
Zheng CHEN
;
Wenjun ZHAO
;
Lirong WEI
;
Yanwen ZHENG
;
Chao HE
;
Yan ZENG
;
Bin YIN
Author Information
1. Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu province, 215123, PR China. yinbin@suda.edu.cn
- Publication Type:Original Article
- Keywords:
VSV-G;
ATRA;
Bystander killing;
Chemoresisitant leukemia cells;
HSV-TK/GCV
- MeSH:
Cell Fusion;
Cell Line;
Coculture Techniques;
Connexin 43;
Cytarabine;
Gap Junctions;
Genetic Therapy;
Glycoproteins*;
Homicide*;
K562 Cells;
Leukemia, Myeloid, Acute;
Membrane Proteins;
Simplexvirus*;
Suicide;
Thymidine*;
Tretinoin;
Up-Regulation;
Vesicular Stomatitis*
- From:Biomolecules & Therapeutics
2014;22(2):114-121
- CountryRepublic of Korea
- Language:English
-
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.
