ATRA And VSV-G Affected Bystander Killing Of Chemoresistant Leukemic Cells By HSV-TK/GCV

Refractoriness of acute myeloid leukemia (AML) cells to chemotherapeuticsrepresents a major clinical barrier. Suicide gene therapy for cancer has been extensivelyinvestigated both in experimental and clinical settings.In this study, we investigated the potential application of herpes simplex virusthymidine kinase/ganciclovir (HSV-TK/GCV) based system to inhibit chemoresistantAML cells. We first generated Ara-C resistant K562cells and doxorubicin-resistantTHP-1cells. We found that the HSV-TK/GCV anticancer system suppressed drugresistant leukemic cells in culture. Chemoresistant AML cell lines displayed similarsensitivity to HSV-TK/GCV. Moreover, HSV-TK/GCV killing of leukemic cells wasaugmented to a mild but significant extent by all-trans retinoic acid (ATRA) withconcomitant upregulation of Connexin43, a major component of gap junctions.Interestingly, HSV-TK/GCV killing was enhanced by expression of vesicular stomatitisvirus G glycoprotein (VSV-G), a fusogenic membrane protein, which also increasedleukemic cell fusion. Co-culture resistant cells expressing HSV-TK and cells stablytransduced with VSV-G showed that expression of VSV-G could promote the bystanderkilling effect of HSV-TK/GCV. Furthermore, combination of HSV-TK/GCV withVSV-G plus ATRA produced more pronounced antileukemia effect.The work we presented here demonstrated for the first time that suicide genetherapy, such as HSV-TK/GCV system, could be used to directly target chemoresistanthuman AML cells, and implied a potential value of VSV-G and ATRA in theenhancement of suicide gene therapy for resistant AML. Our findings may besuggestive of potential improvements in the treatment for chemoresistant AML.