Vakana Eliza, Platanias Leonidas C
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology/Oncology, Northwestern University Medical School and Jesse Brown VA Medical Center, Chicago, IL 60611, USA.
Oncotarget. 2011 Dec;2(12):1322-8. doi: 10.18632/oncotarget.413.
The abnormal BCR-ABL oncoprotein is a constitutively active tyrosine kinase driving aberrant proliferation of transformed hematopoietic cells. BCR-ABL regulates activation of many mitogenic and pro-survival pathways, including the PI 3'K/AKT/mTOR pathway that controls various effectors and regulates initiation of mRNA translation in mammalian cells. Although tyrosine kinase inhibitors (TKIs) that target the ABL kinase domain have remarkable clinical activity and have dramatically changed the natural history of Ph+ leukemias, resistance to these agents also develops via a wide range of mechanisms. Efforts to target the PI3'K/AKT/mTOR signaling pathway using kinase inhibitors have been the focus of extensive ongoing investigations by several research groups. Here we review the effects of activation of the AMPK kinase, which regulates downstream targeting and inhibition of mTOR. The potential for future clinical-translational applications of AMPK activators such as AICAR, metformin and resveratrol for the treatment of chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) are discussed.
异常的BCR-ABL癌蛋白是一种组成型活性酪氨酸激酶，驱动转化造血细胞的异常增殖。BCR-ABL调节许多促有丝分裂和促生存途径的激活，包括PI 3'K/AKT/mTOR途径，该途径控制各种效应器并调节哺乳动物细胞中mRNA翻译的起始。尽管靶向ABL激酶结构域的酪氨酸激酶抑制剂（TKIs）具有显著的临床活性，并极大地改变了Ph+白血病的自然病程，但对这些药物的耐药性也通过多种机制产生。使用激酶抑制剂靶向PI3'K/AKT/mTOR信号通路的努力一直是几个研究小组正在进行的广泛研究的重点。在这里，我们综述了AMPK激酶激活的作用，它调节mTOR的下游靶向和抑制。讨论了AICAR、二甲双胍和白藜芦醇等AMPK激活剂在慢性粒细胞白血病（CML）和Ph+急性淋巴细胞白血病（ALL）治疗中的未来临床转化应用潜力。
