title: Vesicular Stomatitis Virus G Glycoprotein and ATRA Enhanced Bystander Killing of Chemoresistant Leukemic Cells by Herpes Simplex Virus Thymidine Kinase/Ganciclovir.
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.
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu province, 215123, PR China.
authors.forename: Chenxi
authors.initials: C
authors.lastname: Hu
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu province, 215123, PR China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu province, 215123, PR China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu province, 215123, PR China.
authors.forename: Lirong
authors.initials: L
authors.lastname: Wei
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu province, 215123, PR China.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou, Jiangsu province, 215123, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: He
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: 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.
authors.forename: Bin
authors.initials: B
authors.lastname: Yin
keywords: ATRA; Bystander killing; Chemoresisitant leukemia cells; HSV-TK/GCV; VSV-G
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