Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
Mol Ther. 2010 Jun;18(6):1130-1142. doi: 10.1038/mt.2010.29. Epub 2010 Feb 23.
We have explored the mechanism by which inhibition of multiple cytoprotective cell-signaling pathways enhance melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) toxicity toward invasive primary human glioblastoma multiforme (GBM) cells, and whether improving adenoviral infectivity/delivery of mda-7/IL-24 enhances therapeutic outcome in animals containing orthotopic xenografted GBM cells. The toxicity of a serotype 5 recombinant adenovirus to express MDA-7/IL-24 (Ad.5-mda-7) was enhanced by combined molecular or small molecule inhibition of mitogen-activated extracellular regulated kinase (MEK)1/2 and phosphatidyl inositol 3-kinase (PI3K) or AKT; inhibition of mammalian target of rapamycin (mTOR) and MEK1/2; and the HSP90 inhibitor 17AAG. Molecular inhibition of mTOR/PI3K/MEK1 signaling in vivo also enhanced Ad.5-mda-7 toxicity. In GBM cells of diverse genetic backgrounds, inhibition of cytoprotective cell-signaling pathways enhanced MDA-7/IL-24-induced autophagy, mitochondrial dysfunction and tumor cell death. Due partly to insufficient adenovirus serotype 5 gene delivery this therapeutic approach has shown limited success in GBM. To address this problem, we employed a recombinant adenovirus that comprises the tail and shaft domains of a serotype 5 virus and the knob domain of a serotype 3 virus expressing MDA-7/IL-24, Ad.5/3-mda-7. Ad.5/3-mda-7 more effectively infected and killed GBM cells in vitro and in vivo than Ad.5-mda-7. Future combinations of these approaches hold promise for developing an effective therapy for GBM.
我们探讨了抑制多种细胞保护信号通路的机制，这些机制增强了黑色素瘤分化相关基因-7/白细胞介素-24（mda-7/IL-24）对侵袭性原发性人胶质母细胞瘤（GBM）细胞的毒性，以及提高腺病毒感染/ mda-7/IL-24 传递是否能增强含有原位异种移植 GBM 细胞的动物的治疗效果。表达 MDA-7/IL-24 的血清型 5 重组腺病毒（Ad.5-mda-7）的毒性通过联合使用丝裂原活化细胞外调节激酶（MEK）1/2 和磷酸肌醇 3-激酶（PI3K）或 AKT 的分子或小分子抑制、哺乳动物雷帕霉素靶蛋白（mTOR）和 MEK1/2 的抑制以及 HSP90 抑制剂 17AAG 来增强。体内 mTOR/PI3K/MEK1 信号转导的分子抑制也增强了 Ad.5-mda-7 的毒性。在具有不同遗传背景的 GBM 细胞中，抑制细胞保护信号通路增强了 MDA-7/IL-24 诱导的自噬、线粒体功能障碍和肿瘤细胞死亡。由于腺病毒血清型 5 基因传递不足，这种治疗方法在 GBM 中的疗效有限。为了解决这个问题，我们采用了一种重组腺病毒，该病毒包含血清型 5 病毒的尾部和轴域以及表达 MDA-7/IL-24 的血清型 3 病毒的旋钮域，即 Ad.5/3-mda-7。Ad.5/3-mda-7 比 Ad.5-mda-7 更有效地感染和杀死体外和体内的 GBM 细胞。这些方法的未来组合有望为开发 GBM 的有效治疗方法提供前景。
