SB225002 Induces Cell Death and Cell Cycle Arrest in Acute Lymphoblastic Leukemia Cells through the Activation of GLIPR1

Abstract

Acute Lymphoblastic Leukemia (ALL) is the most frequent childhood malignancy. In the effort to find new anti-leukemic agents, we evaluated the small drug SB225002 (N-(2-hydroxy-4-nitrophenyl)-N’-(2-bromophenyl)urea). Although initially described as a selective antagonist of CXCR2, later studies have identified other cellular targets for SB225002, with potential medicinal use in cancer. We found that SB225002 has a significant pro-apoptotic effect against both B- and T-ALL cell lines. Cell cycle analysis demonstrated that treatment with SB225002 induces G2-M cell cycle arrest. Transcriptional profiling revealed that SB225002-mediated apoptosis triggered a transcriptional program typical of tubulin binding agents. Network analysis revealed the activation of genes linked to the JUN and p53 pathways and inhibition of genes linked to the TNF pathway. Early cellular effects activated by SB225002 included the up-regulation of GLIPR1, a p53-target gene shown to have pro-apoptotic activities in prostate and bladder cancer. Silencing of GLIPR1 in B- and T-ALL cell lines resulted in increased resistance to SB225002. Although SB225002 promoted ROS increase in ALL cells, antioxidant N-Acetyl Cysteine pre-treatment only modestly attenuated cell death, implying that the pro-apoptotic effects of SB225002 are not exclusively mediated by ROS. Moreover, GLIPR1 silencing resulted in increased ROS levels both in untreated and SB225002-treated cells. In conclusion, SB225002 induces cell cycle arrest and apoptosis in different B- and T-ALL cell lines. Inhibition of tubulin function with concurrent activation of the p53 pathway, in particular, its downstream target GLIPR1, seems to underlie the anti-leukemic effect of SB225002.

The stem cell factor SALL4 is an essential transcriptional regulator in mixed lineage leukemia-rearranged leukemogenesis

“…3 c). Cdkn1a has been known to be a potent cyclin-dependent kinase inhibitor that blocks cell cycle progression in the G1 phase [ 32 ], while Trp53inp1 and Glipr1 are p53-induced pro-apoptotic genes that also mediate apoptosis and G1 cell cycle arrest [ 33 , 34 ]. Similarly, Wig1 regulates cell cycle arrest and cell death through the regulation of p53 targets FAS and 14-3-3σ mRNA levels [ 35 ].…”

Francisella novicida inhibits spontaneous apoptosis and extends human neutrophil lifespan

“…To our surprise, SB225002, alone or in combination with Reparixin, favored survival of the uninfected control PMNs yet increased apoptosis in the presence of iPMN-CM. What accounts for these paradoxical results is unknown, but it is worth noting that several other targets of SB225002 were recently identified [59]. Taken together, our data suggest that CXCL8 contributes to, but is not essential for, apoptosis inhibition by F. novicida.…”

Interleukin‑8 promotes prostate cancer bone metastasis through upregulation of bone sialoprotein

“…An MTT assay was used in order to provide a quantitative measure of the number of cells with metabolically active mitochondria, as it is based on the mitochondrial reduction of a tetrazolium bromide salt [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (13,14). DU145 and LNCaP cells (3,000 cells/well) were plated in triplicate in 96-well culture plates in RPMI-1640 containing 10% FBS and subsequently incubated with different concentrations of the IL-8 receptor inhibitor SB225002 (0.2, 0.4, 0.8, 1.6, 3.2, 6.4 µM and control dimethyl sulfoxide (DMSO) 0.01%) at 37°C.…”