Department of Hematology, Affiliated Hospital of Guizhou Medical University, Laboratory of Hematopoietic Stem Cell Transplantation Centre of Guizhou Province, Guiyang, Guizhou, China; College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou, China.
Department of Hematology, Affiliated Hospital of Guizhou Medical University, Laboratory of Hematopoietic Stem Cell Transplantation Centre of Guizhou Province, Guiyang, Guizhou, China; Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
Biomed Pharmacother. 2018 Apr;100:509-520. doi: 10.1016/j.biopha.2018.02.039. Epub 2018 Feb 23.
To improve the treatment outcomes of acute myeloid leukemia (AML), epigenetic modification has been widely tested and used in recent years. However, drug-resistance is still a choke point to cure the malignancy. The growth factor independent 1 transcriptional repressor (GFI-1), as a zinc-finger transcriptional repressor, can bind histone deacetylases to allow the transcriptional repression. According to the finding of our study, AML patients with low level of GFI-1 not only implicated poor prognosis but also caused Panobinostat-resistance. In our prevent study revealed that heme oxygenase-1(HO-1) was one of the main factors leading to chemotherapy sensitivity to AML. Thus, this study tried to test the correlation between GFI-1 and HO-1. Our study discovered that AML patients with lower expression of GFI-1 had higher level of HO-1, HDAC1, HDAC2 and HDAC3, which resulted in poor prognosis in AML. The results of the in vitro study were the same. Panobinostat is a promising new class of anti-cancer drugs in AML. However, knocking down GFI-1 by siRNA could eliminate the Panobinostat-induced cell apoptosis. Subsequently, we utilized ZnPP to down regulate the level of HO-1, finding that the Panobinostat-resistance between the low level of GFI-1 and empty vector had eased. After further exploring the mechanism, it could be found that with knock down GFI-1, the phosphorylation of Akt and PI3K could be activated. Subsequently, Akt pathway and HO-1 inhibitor were utilized respectively and the resistance was reversed. It suggested that the resistance of Panobinostat to AML cells at low level of GFI-1 was mainly due to up-regulated level of HO-1 through the PI3K-Akt pathway.
为了改善急性髓细胞白血病（AML）的治疗效果，近年来广泛测试和应用了表观遗传修饰。然而，耐药性仍然是治愈这种恶性肿瘤的一个瓶颈。生长因子独立 1 转录抑制因子（GFI-1）作为一种锌指转录抑制因子，可以与组蛋白去乙酰化酶结合，从而允许转录抑制。根据我们的研究发现，GFI-1 水平低的 AML 患者不仅预后不良，而且还导致 Panobinostat 耐药。在我们的预防研究中发现，血红素加氧酶-1（HO-1）是导致 AML 对化疗敏感性的主要因素之一。因此，本研究试图测试 GFI-1 和 HO-1 之间的相关性。我们的研究发现，GFI-1 表达较低的 AML 患者 HO-1、HDAC1、HDAC2 和 HDAC3 水平较高，导致 AML 预后不良。体外研究结果相同。Panobinostat 是 AML 中一种有前途的新型抗癌药物。然而，通过 siRNA 敲低 GFI-1 可以消除 Panobinostat 诱导的细胞凋亡。随后，我们利用 ZnPP 下调 HO-1 水平，发现低水平 GFI-1 和空载体之间的 Panobinostat 耐药性有所缓解。进一步探索其机制发现，敲低 GFI-1 后，Akt 和 PI3K 的磷酸化可以被激活。随后，分别利用 Akt 通路和 HO-1 抑制剂，耐药性得到逆转。这表明在 GFI-1 水平低的情况下，Panobinostat 对 AML 细胞的耐药性主要是由于 HO-1 通过 PI3K-Akt 通路的上调。
