MER1, a novel organic arsenic derivative, has potent PML-RARalpha-independent cytotoxic activity against leukemia cells.
Arsenic trioxide (ATO) is an inorganic arsenic derivative that is highly effective against PML-RARalpha-positive leukemia but much less against other hematological malignancies. We synthesized an organic arsenic derivative (OAD), S-dimethylarsino-thiosuccinic acid (MER1), which offers a superior toxicity profile and comparable in vitro activity relative to ATO. In Swiss Webster mice, maximally-tolerated cumulative dose of MER1 when given i.v. for 5 days was 100 mg/kg/d. We demonstrated that MER1 induced apoptosis and dose- and time-dependent inhibition of survival and growth in a panel of myeloid leukemia cell lines. Unlike ATO, this activity was independent of PML-RARalpha status and was not associated with induction of myeloid maturation. In NB4 and HL60 cells, MER1 and ATO induced caspase activation and dissipation of mitochondrial transmembrane potential. At the same time, MER1 induced generation of reactive oxygen species (ROS) and cell cycle arrest in G2/M phase and proved to be more potent than ATO at inducing apoptosis. ROS generation and intracellular glutathione levels were key modulators of MER1-induced cytotoxicity as evidenced by abrogation of apoptosis in myeloid leukemia cell lines pretreated with the disulfide bond-reducing agent dithiothreitol or the radical scavenger N-acetyl-L-cysteine. Collectively, these data indicate that MER1 induces apoptosis in PML-RARalpha-positive and -negative myeloid leukemia cells by enhancing oxidative stress. This agent, therefore, combines low in vivo toxicity with formidable in vitro pro-apoptotic ROS-mediated activity, and may represent a novel OAD suitable for clinical development against a variety of hematological malignancies.
Golemovic
Mirna
M
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Unit 428, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Quintás-Cardama
Alfonso
A
Manshouri
Taghi
T
Orsolic
Nada
N
Duzkale
Hatice
H
Johansen
Mary
M
Freireich
Emil J
EJ
Kantarjian
Hagop
H
Zingaro
Ralph A
RA
Verstovsek
Srdan
S
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000494:pharmacology*; D020169:Caspases / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D020714:Maximum Tolerated Dose; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013386:Succinates / Q000008:administration & dosage / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001152:Arsenicals; D015514:Oncogene Proteins, Fusion; D010087:Oxides; D017382:Reactive Oxygen Species; C552033:S-dimethylaminoarsino-thiosuccinic acid; D013386:Succinates; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D020169:Caspases; D000077237:Arsenic Trioxide