Adenovirus-mediated delivery of the human IFN-γ gene potentiates the cytotoxicity of daunorubicin against leukemic cells through downregulation of the α4β1 integrin/ILK/apoptosis pathway

摘要

The recurrence of acute myeloid leukemia (AML) is primarily attributed to drug resistance and minimal residual disease. In addition, adhesion of hematopoietic tumor cells to bone marrow extracellular matrix via β1 integrins (α4β1 and α5β1) is crucial in this process. In the current study, the viability and antiapoptotic ability of U937 cells exposed to daunorubicin (DNR) were shown to be enhanced when cocultured with the mesenchymal stem cells (MSCs) or MSCs transduced with a recombinant adeno-LacZ vector (MSCs-LacZ), followed by upregulation of the adhesion rate of leukemic cells. Notably, cell viability, antiapoptotic and adhesive ability were reversed when U937 cells were cocultured with the MSCs transduced with a recombinant adeno-IFN-γ vector (MSCs-IFN-γ). Transwell assay showed that cell-cell contact is essential for the protective effects of unmodified MSC and the antitumor effects of IFN-γ-expressing MSCs. Western blot analysis and caspase activity assay results indicated that the α4β1 integrin/ILK/apoptosis pathway contributes to the combination effects of DNR and MSCs-IFN-γ, which was further confirmed by the results of the α4β1 integrin siRNA experiments. Thus, gene-modified MSCs expressing IFN-γ may enhance the cytotoxicity of DNR against leukemic cells through downregulation of the α4β1 pathway and may present a novel promising therapeutic strategy for AML.