title: The organic arsenic derivative GMZ27 induces PML-RARα-independent apoptosis in myeloid leukemia cells.
abstract: Arsenic trioxide (ATO) is an inorganic arsenic derivative that is very effective against acute promyelocytic leukemia. However, organic arsenic derivatives (OAD) have a more favorable toxicity profile than ATO. We herein characterized dipropil-S-glycerol arsenic (GMZ27), a novel OAD. GMZ27 had potent antiproliferative activity against human acute myeloid leukemia (AML) cell lines that was higher than that of ATO. In contrast to ATO, GMZ27 only marginally induced maturation of leukemia cells and had no effect on the cell cycle. The anti-leukemia activity of GMZ27 against AML cells was independent of the presence of the PML-RARα fusion protein. GMZ27 dissipates mitochondrial transmembrane potential, and induces cleavage of caspase 9 and activation of caspase 3 without altering the expression levels of (BCL-2), BAX and BCL-xl. GMZ27 induces the formation of intracellular superoxide, a reactive oxygen species (ROS) which plays a major role in the antileukemia activity of this OAD. In addition to ROS generation, GMZ27 concomitantly reduces intracellular glutathione which markedly weakens the cellular antioxidant capacity, thus enhancing the detrimental intracellular effects of ROS production. These results indicate that GMZ27 induces apoptosis in AML cells in a PML-RARα-independent fashion, through the induction of ROS production. This activity provides the rationale for the testing of GMZ27 in patients with AML.
authors: Anderson Cancer Center, Department of Leukemia, Unit 428, 1515 Holcombe Blvd., Houston, TX 77030, USA.
authors: Xiaodong
authors: X
authors: Cheng
authors: Alfonso
authors: A
authors: Quintás-Cardama
authors: Mirna
authors: M
authors: Golemovic
authors: Ralph
authors: R
authors: Zingaro
authors: Ming-Zhang
authors: MZ
authors: Gao
authors: Emil J
authors: EJ
authors: Freireich
authors: Michael
authors: M
authors: Andreeff
authors: Hagop M
authors: HM
authors: Kantarjian
authors: Srdan
authors: S
authors: Verstovsek
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D053453:Caspase 9 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D015479:Leukemia, Myelomonocytic, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis*; D010087:Oxides / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D053453:Caspase 9; D000077237:Arsenic Trioxide; D010100:Oxygen