Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, People's Republic of China.
Department of Hematology, Hangzhou First People's Hospital, Hangzhou, 310006, Zhejiang Province, People's Republic of China.
Sci Rep. 2017 Jun 6;7(1):2894. doi: 10.1038/s41598-017-03058-4.
Patients with secondary acute myeloid leukemia (sAML) arising from myelodysplastic syndromes have a poor prognosis marked by an increased resistance to chemotherapy. An urgent need exists for adjuvant treatments that can enhance or replace current therapeutic options. Here we show the potential of LB100, a small-molecule protein phosphatase 2 A (PP2A) inhibitor, as a monotherapy and chemosensitizing agent for sAML using an in-vitro and in-vivo approach. We demonstrate that LB100 decreases cell viability through caspase activation and G2/M cell-cycle arrest. LB100 enhances daunorubicin (DNR) cytotoxicity resulting in decreased xenograft volumes and improved overall survival. LB100 profoundly upregulates miR-181b-1, which we show directly binds to the 3' untranslated region of Bcl-2 mRNA leading to its translational inhibition. MiR-181b-1 ectopic overexpression further diminishes Bcl-2 expression leading to suppression of sAML cell growth, and enhancement of DNR cytotoxicity. Our research highlights the therapeutic potential of LB100, and provides new insights into the mechanism of LB100 chemosensitization.
继发急性髓系白血病（sAML）患者源自骨髓增生异常综合征，其预后较差，对化疗的耐药性增加。迫切需要辅助治疗方法，以增强或替代目前的治疗选择。在这里，我们通过体外和体内方法展示了小分子蛋白磷酸酶 2A（PP2A）抑制剂 LB100 作为 sAML 的单药治疗和化疗增敏剂的潜力。我们证明 LB100 通过半胱天冬酶激活和 G2/M 细胞周期阻滞降低细胞活力。LB100 增强柔红霉素（DNR）的细胞毒性，导致异种移植物体积减小和总生存期延长。LB100 显著上调 miR-181b-1，我们证明其直接结合 Bcl-2 mRNA 的 3'非翻译区，导致其翻译抑制。miR-181b-1 的异位过表达进一步降低 Bcl-2 的表达，从而抑制 sAML 细胞生长，并增强 DNR 的细胞毒性。我们的研究强调了 LB100 的治疗潜力，并为 LB100 化疗增敏的机制提供了新的见解。
