In vitro activity of dimethylarsinic acid against human leukemia and multiple myeloma cell lines

Hatice Duzkale, Iman Jilani, Nada Orsolic, Ralph A. Zingaro, Mirna Golemovic, Francis J. Giles, Hagop Kantarjian, Maher Albitar, Emil J. Freireich, Srdan Verstovsek*

*Corresponding author for this work

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Purpose: Arsenic trioxide (As2O3), an inorganic arsenic compound, has recently been approved for the treatment of relapsed or refractory acute promyelocytic leukemia. However, systemic toxicity associated with As2O3 treatment remains a problem. Inorganic arsenic is detoxified in vivo by methylation reactions into organic arsenic compounds that are less toxic. Methods and results: We investigated the antiproliferative and cytotoxic activity of dimethylarsinic acid (DMAA), an organic arsenic derivative and major metabolic by-product of As2O3, against a panel of eight leukemia and multiple myeloma cell lines. As2O3 was tested in comparison. In clonogenic assay, the average concentration of DMAA that suppressed cell colony growth by 50% was 0.5-1 mM, while for As2O3 it was on average 1-2 μM. At those concentrations DMAA and As2O3 had significantly less effect on colony growth of normal progenitor cells. Cytotoxic doses of DMAA and As2O3 in 3-day trypan blue dye exclusion assay experiments were similar to doses effective in clonogenic assay. Assessment of apoptosis by annexin V assay revealed a high rate of apoptosis in all cell lines treated with DMAA and As2O3, but significantly less effect on normal progenitor cells. DMAA, unlike As2O3, had no effect on the maturation of leukemic cells. Conclusions: DMAA exerts differential antiproliferative and cytotoxic activity against leukemia and multiple myeloma cells, with no significant effect on normal progenitor cells. However, concentrations of DMAA needed to achieve such efficacy are up to 1000 times those of As2O3. Evaluation of novel organic arsenic that would combine the high efficacy of As2O3 and the low toxicity of DMAA is warranted.

Original languageEnglish (US)
Pages (from-to)427-432
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume51
Issue number5
StatePublished - May 1 2003

Keywords

  • Arsenic trioxide
  • Dimethylarsinic acid
  • Leukemia
  • Multiple myeloma

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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