Abstract 5378: SB225002 induces apoptosis in acute lymphoid leukemia cells

Abstract

Abstract Acute Lymphoblastic Leukemia (ALL) is the most frequent childhood malignancy. We have recently shown that the leukemic bone marrow (BM) contains high levels of interleukin-8 (IL-8), whose cognate receptor CXCR2 is expressed by most primary ALL cells. ALL cell lines are sensitive to SB225002 (N-(2-hydroxy-4-nitrophenyl)-N’-(2-bromophenyl)urea), a CXCR2 antagonist. Surprisingly, the inhibitory effect of this drug was found to be independent of CXCR2 expression by leukemic cells. The current study was conducted to determine the mechanism of action of SB225002 against ALL cells, using as prototype the T-ALL cell line Jurkat. Cell cycle analysis showed that SB225002 induces G2-M cell cycle arrest. Transcriptional profiling by microarray analysis revealed that SB225002 induces 174 genes and represses 41 genes. SB225002 induced-apoptosis triggered a transcriptional program of genes involved in activation of the JUN and p53 pathways and inhibition of the TNFα pathway. Results were further confirmed by Q-PCR and/or Western blot analysis. Treatment of Jurkat cells with SB225002 also induced the activation of phospho-p44/42 MAPK (ERK1/2), which was suspected to be an anti-apoptotic pathway triggered by injured cells. In fact, the inhibition of ERK1/2 with pharmacologic inhibitors, in combination with SB225002, resulted in the enhancement of apoptosis, suggesting the blockage of ERK1/2 pathway as a strategy to increase the sensitivity of ALL cells toward SB225002. Connectivity Map analysis of the SB225002 gene signature demonstrates a positive correlation with the signatures for PI3K and HSP90 inhibitors (connectivity score 1 and 0.944, respectively), which mediate apoptosis through effects on AKT, TNFα and NF-κB, while SB225002's mediated-apoptosis demonstrated only to inhibit TNFα pathway. Furthermore, SB225002 gene signature demonstrates a positive correlation with Nocodazole and Podophyllotoxin (connectivity score 0.895 and 0.859, respectively), which are inducers of cancer cell apoptosis by interfering with microtubule polymerization and inhibiting topoisomerase II, respectively. Our data demonstrate for the first time that JUN, p53, and TNFα pathways are modulated by SB225002, and that ALL cells are sensitized to SB225002-induced apoptosis after phospho-p44/42 MAPK inhibition. Overall these data support SB225002's therapeutic potential in ALL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5378. doi:10.1158/1538-7445.AM2011-5378