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Vesicular Stomatitis Virus G Glycoprotein and ATRA Enhanced Bystander Killing of Chemoresistant Leukemic Cells by Herpes Simplex Virus Thymidine Kinase/Ganciclovir
Biomolecules & Therapeutics ; : 114-121, 2014.
Article in English | WPRIM | ID: wpr-228917
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.
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Full text: Available Index: WPRIM (Western Pacific) Main subject: Suicide / Thymidine / Tretinoin / Glycoproteins / Genetic Therapy / Leukemia, Myeloid, Acute / Up-Regulation / Cell Fusion / Cell Line / Simplexvirus Language: English Journal: Biomolecules & Therapeutics Year: 2014 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Main subject: Suicide / Thymidine / Tretinoin / Glycoproteins / Genetic Therapy / Leukemia, Myeloid, Acute / Up-Regulation / Cell Fusion / Cell Line / Simplexvirus Language: English Journal: Biomolecules & Therapeutics Year: 2014 Type: Article