Arginine butyrate increases the cytotoxicity of DAB389IL-2 in leukemia and lymphoma cells by upregulation of IL-2Rβ gene

Richard H. Shao, Xuejun Tian, Gullu Gorgun, Alexander G. Urbano, Francine M. Foss

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

DAB389IL-2 (ONTAK) is a fusion protein consisting of the ADP-ribosyltransferase and membrane translocating domains of native diphtheria toxin and the full-length sequence for interleukin-2 (IL-2) gene. In vitro data demonstrates that DAB389IL-2 is cytotoxic to cells expressing the high affinity IL-2 receptor (IL-2R). In Phases I and II clinical trials of patients whose tumor cells express a component of the IL-2R, the response rates were 18% for B-cell non-Hodgkin lymphoma (NHL) and 30% for cutaneous T-cell lymphoma (CTCL). In this study, we examined the effects of arginine butyrate on IL-2R expression and susceptibility of leukemia cells to intoxication by DAB389IL-2. We demonstrate that the p75 subunit of the IL-2R (IL-2Rβ) is upregulated in the presence of low concentrations of arginine butyrate (0.06mM) which had no direct growth inhibitory effect on the cells. To explore mechanisms of this upregulation, we examined the effect of 0.06mM arginine butyrate on relevant transcriptional elements and on histone deacetylase and found activation of cAMP response element (CRE) but not NFAT or NFKB, as well as inhibition of histone deacetylase (HDAC). Our results suggest that the effects of physiologically achievable concentrations of butyrate on IL-2R expression could be exploited to enhance the susceptibility of intermediate and low-affinity IL-2R expressing leukemia cells to DAB389IL-2.

Original languageEnglish (US)
Pages (from-to)1077-1083
Number of pages7
JournalLeukemia Research
Volume26
Issue number12
DOIs
StatePublished - Dec 1 2002

Keywords

  • Arginine butyrate
  • Cutaneous T-cell lymphoma (CTCL)
  • DABIL-2
  • Histone deacetylase (HDAC) inhibitor
  • IL-2 receptor (IL-2R)
  • Interleukin-2 (IL-2)
  • ONTAK
  • Signal transduction pathway
  • T-cell lymphoma/leukemia

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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