Arginine butyrate increases the cytotoxicity of DAB(389)IL-2 in leukemia and lymphoma cells by upregulation of IL-2Rbeta gene.
DAB(389)IL-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 DAB(389)IL-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 DAB(389)IL-2. We demonstrate that the p75 subunit of the IL-2R (IL-2Rbeta) 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 DAB(389)IL-2.
Shao
Richard H
RH
Hematology-Oncology Department, New England Medical Center, Tufts University, Boston, MA, USA.
Tian
Xuejun
X
Gorgun
Gullu
G
Urbano
Alexander G
AG
Foss
Francine M
FM
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002087:Butyrates / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000235:genetics; D004167:Diphtheria Toxin / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007376:Interleukin-2 / Q000633:toxicity*; D053646:Interleukin-2 Receptor beta Subunit; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D018123:Receptors, Interleukin / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000633:toxicity*; D020218:Response Elements / Q000502:physiology; D015290:Second Messenger Systems / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D002087:Butyrates; D004167:Diphtheria Toxin; C508020:IL2RB protein, human; D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit; D018123:Receptors, Interleukin; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox; D001120:Arginine; D000242:Cyclic AMP; C033018:arginine butyrate