title: Concurrent targeting Akt and sphingosine kinase 1 by A-674563 in acute myeloid leukemia cells.
abstract: 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.
authors.affiliation: Xiangya Hospital, Central South University, Changsha, China; Shaoyang Central Hospital, Hunan Province, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Gao
authors.affiliation: Xiangya Hospital, Central South University, Changsha, China. Electronic address: wangguangping45@sina.com.
authors.forename: Guangping
authors.initials: G
authors.lastname: Wang
authors.affiliation: The Third Xiangya Hospital, Central South University, Changsha, 410013, China. Electronic address: fuyunfeng33163@163.com.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Fu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D020298:U937 Cells; D000099157:Sphingosine Kinase
chemical_list: D000970:Antineoplastic Agents; D053148:Caspase 3; D007191:Indazoles; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D000099157:Sphingosine Kinase; C000619514:A-674563
keywords: A-674563; Acute myeloid leukemia; Akt; Sphingosine kinase 1