Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Autophagy. 2010 Oct;6(7):976-8. doi: 10.4161/auto.6.7.13117. Epub 2010 Oct 23.
We analyzed the cellular and molecular effects of two different histone deacetylase inhibitors (HDACi), MGCD0103 and vorinostat, in combination with GX15-070, a BH3-mimetic, in acute myeloid leukemia (AML) cell lines and primary AML cells, and demonstrated that the combination has a synergistic antileukemia effect. We observed that in addition to apoptosis, autophagy also accounts for the observed nonapoptotic decrease of cell viability. Mechanistically, we established a role for calpain activity and ER-located caspase signaling in the induction of both autophagy and apoptosis following this combination of drugs. These findings reveal that for this specific combination, autophagy plays a positive role in inducing cytotoxicity, and that the involved ER signaling networks, as well as their clinical relevance, should be further studied in both preclinical and clinical trials of leukemia and other malignancies.
我们分析了两种不同的组蛋白去乙酰化酶抑制剂（HDACi），即 MGCD0103 和 vorinostat，与 BH3 模拟物 GX15-070 联合应用于急性髓系白血病（AML）细胞系和原代 AML 细胞中的细胞和分子效应，并证实该联合具有协同抗白血病作用。我们观察到，除了凋亡，自噬也解释了观察到的非凋亡细胞活力下降。从机制上讲，我们确定钙蛋白酶活性和内质网定位的半胱天冬酶信号在药物联合诱导自噬和凋亡中发挥作用。这些发现表明，对于这种特定的组合，自噬在诱导细胞毒性方面发挥了积极作用，并且涉及的内质网信号网络及其临床相关性应在白血病和其他恶性肿瘤的临床前和临床试验中进一步研究。
