MER1, a novel organic arsenic derivative, has potent PML-RARα- independent cytotoxic activity against leukemia cells View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2009-05-26

AUTHORS

Mirna Golemovic, Alfonso Quintás-Cardama, Taghi Manshouri, Nada Orsolic, Hatice Duzkale, Mary Johansen, Emil J. Freireich, Hagop Kantarjian, Ralph A. Zingaro, Srdan Verstovsek

ABSTRACT

Arsenic trioxide (ATO) is an inorganic arsenic derivative that is highly effective against PML-RARα-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 IV 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-RARα 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-RARα-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. More... »

PAGES

402-412

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10637-009-9267-z

DOI

http://dx.doi.org/10.1007/s10637-009-9267-z

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1015404446

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/19468689


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32 schema:description Arsenic trioxide (ATO) is an inorganic arsenic derivative that is highly effective against PML-RARα-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 IV 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-RARα 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-RARα-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.
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44 ROS generation
45 Swiss Webster mice
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49 acid
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53 agents
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56 arsenic derivatives
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67 data
68 days
69 derivatives
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71 dissipation
72 disulfide bond-reducing agent dithiothreitol
73 dithiothreitol
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80 induction
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83 leukemia
84 leukemia cell lines
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88 malignancy
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96 organic arsenic derivative
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99 panel
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102 potential
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106 same time
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