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.
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.
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腺病毒介导的人 IFN-γ 基因传递通过下调 α4β1 整合素/ILK/凋亡途径增强柔红霉素对白血病细胞的细胞毒性
DOI：
10.3892/ol.2013.1749
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发表时间：
2014-02
期刊：
影响因子：
2.9
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Zhang J;Wang H;Wang L;Wang WD;Geng QR;Lu Y
急性髓系白血病(AML)的复发主要归因于耐药和微小残留病。此外，造血肿瘤细胞通过β-1整合素(α-4-β-1和α-5-β-1)与骨髓细胞外基质的黏附在此过程中起着至关重要的作用。在本研究中，柔红霉素(DNR)与骨髓间充质干细胞(MSCs)或重组腺病毒载体转导的MSCs(MSCs-LacZ)共培养可增强U937细胞的活力和抗凋亡能力，并上调白血病细胞的粘附率。值得注意的是，当U937细胞与重组腺病毒-干扰素-γ载体(MSCs-干扰素-γ)转导的骨髓间充质干细胞共同培养时，细胞活力、抗凋亡和黏附能力被逆转。Transwell实验表明，细胞-细胞接触对于未修饰的MSCs的保护作用和表达干扰素-γ的MSCs的抗肿瘤作用是必不可少的。免疫印迹分析和半胱氨酸天冬氨酸氨基转移酶活性检测结果表明，α4β1整合素/ILK/细胞凋亡通路参与了柔红霉素与MSCs干扰素γ的联合作用，α4β1整合素siRNA实验结果进一步证实了这一点。因此，表达干扰素-γ的基因修饰的骨髓间充质干细胞可能通过下调α-4-β-1途径增强柔红霉素对白血病细胞的杀伤作用，为治疗急性髓细胞白血病提供了一种新的有前景的治疗策略。
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.
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白血病细胞中通过 GSK3beta 激活建立的新的 α5β1 整合素依赖性生存途径。
影响因子：
3.7
作者：
De Toni-Costes F;Despeaux M;Bertrand J;Bourogaa E;Ysebaert L;Payrastre B;Racaud-Sultan C
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影响因子：
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DOI：
10.1634/stemcells.2008-0084
发表时间：
2008-09
期刊：
Stem cells (Dayton, Ohio)
影响因子：
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作者：
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