Xu Lin, Zhang Yanan, Gao Meng, Wang Guangping, Fu Yunfeng
Xiangya Hospital, Central South University, Changsha, China; Shaoyang Central Hospital, Hunan Province, China.
The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
Biochem Biophys Res Commun. 2016 Apr 15;472(4):662-8. doi: 10.1016/j.bbrc.2016.02.094. Epub 2016 Feb 23.
Akt signaling plays a pivotal role in acute myeloid leukemia (AML) development and progression. In the present study, we evaluated the potential anti-AML activity by a novel Akt kinase inhibitor A-674563. Our results showed that A-674563 dose-dependently inhibited survival and proliferation of U937 AML cells and six lines of human AML progenitor cells, yet sparing human peripheral blood mononuclear leukocytes (PBMCs). A-674563 activated caspase-3/9 and apoptosis in the AML cells. Reversely, the pan-caspase inhibitor z-VAD-CHO dramatically alleviated A-674563-induced AML cell apoptosis and cytotoxicity. For the molecular study, we showed that A-674563 blocked Akt activation in U937 cells and human AML progenitor cells. Further, A-674563 decreased sphingosine kinase 1 (SphK1) activity in above AML cells to deplete pro-survival sphingosine-1-phosphate (S1P) and boost pro-apoptotic ceramide production. Such an effect on SphK1 signaling by A-674563 appeared independent of Akt blockage. Significantly, K6PC-5, a novel SphK1 activator, or supplement with S1P attenuated A-674563-induced ceramide production, and subsequent U937 cell death and apoptosis. Importantly, intraperitoneal injection of A-674563 at well-tolerated doses suppressed U937 leukemic xenograft tumor growth in nude mice, whiling significantly improving the animal survival. The results of the current study demonstrate that A-674563 exerts potent anti-leukemic activity in vitro and in vivo, possibly via concurrent targeting Akt and SphK1 signalings.
Akt信号通路在急性髓系白血病（AML）的发生和发展中起关键作用。在本研究中，我们评估了新型Akt激酶抑制剂A-674563的潜在抗AML活性。我们的结果表明，A-674563剂量依赖性地抑制U937 AML细胞和6株人AML祖细胞的存活和增殖，但对人外周血单个核白细胞（PBMC）没有影响。A-674563激活AML细胞中的caspase-3/9并诱导细胞凋亡。相反，泛半胱天冬酶抑制剂z-VAD-CHO显著减轻了A-674563诱导的AML细胞凋亡和细胞毒性。在分子研究中，我们发现A-674563阻断U937细胞和人AML祖细胞中的Akt激活。此外，A-674563降低上述AML细胞中的鞘氨醇激酶1（SphK1）活性，以消耗促存活的鞘氨醇-1-磷酸（S1P）并促进促凋亡神经酰胺的产生。A-674563对SphK1信号通路的这种作用似乎独立于Akt阻断。值得注意的是，新型SphK1激活剂K6PC-5或补充S1P可减弱A-674563诱导的神经酰胺产生，以及随后的U937细胞死亡和凋亡。重要的是，以耐受性良好的剂量腹腔注射A-674563可抑制裸鼠中U937白血病异种移植肿瘤的生长，同时显著提高动物存活率。当前研究结果表明，A-674563在体外和体内均具有强大的抗白血病活性，可能是通过同时靶向Akt和SphK1信号通路来实现的。
