Department of Pediatrics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
Blood. 2010 Jan 28;115(4):824-33. doi: 10.1182/blood-2009-07-233445. Epub 2009 Nov 23.
The serine/threonine Pim kinases are up-regulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre-T-LBL/T-ALL) being highly sensitive. Incubation of pre-T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27(Kip1), apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phospho-p70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre-T-LBL cells. In immunodeficient mice carrying subcutaneous pre-T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre-T-LBL.
丝氨酸/苏氨酸 Pim 激酶在特定的血液肿瘤中上调，在关键信号转导途径中发挥重要作用，包括受 MYC、MYCN、FLT3-ITD、BCR-ABL、HOXA9 和 EWS 融合调控的途径。我们证明，新型苯甲亚甲基-噻唑烷-2,4-二酮小分子 Pim 激酶抑制剂 SMI-4a 可杀伤广泛的髓系和淋巴系细胞系，其中前体 T 细胞淋巴母细胞白血病/淋巴瘤（pre-T-LBL/T-ALL）对其高度敏感。将 pre-T-LBL 细胞与 SMI-4a 孵育可诱导 G1 期细胞周期停滞，这是由于 p27(Kip1) 的剂量依赖性诱导、线粒体途径的细胞凋亡以及哺乳动物雷帕霉素靶蛋白 C1（mTORC1）途径的抑制所致，该途径的抑制基于磷酸化 p70 S6K 和磷酸化 4E-BP1、2 的减少，这是该酶的底物。此外，发现用 SMI-4a 处理这些细胞可诱导细胞外信号调节激酶 1/2（ERK1/2）的磷酸化，并且 SMI-4a 与丝裂原激活蛋白激酶激酶 1/2（MEK1/2）抑制剂的联合使用在杀伤 pre-T-LBL 细胞方面具有高度协同作用。在携带皮下 pre-T-LBL 肿瘤的免疫缺陷小鼠中，每日两次用 SMI-4a 治疗可显著延迟肿瘤生长，而体重、血细胞计数或化学物质没有任何变化。我们的数据表明，抑制 Pim 蛋白激酶可能被开发为治疗 pre-T-LBL 的治疗策略。
