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Ntial cellular approach for normal cells, its therapeutic targeting in cancer appears unlikely. Nevertheless, recently, a class of drugs targeting rDNA transcription has shown guarantee as novel cancer therapy in pre-clinical models [10, 11, 12, 13, 14, 15]. These studies have shown that therapeutically inhibiting rDNA transcription with these drugs selectively kills cancer cells and spares standard cells. CX-5461 could be the initially potent and selective BMP-2 Inhibitors Related Products inhibitor of RNA pol I transcription [16]. Recently, the rRNA synthesis inhibitors, CX-5461 and BMH-21, have shown therapeutic prospective in unique cancer models [10, 13, 17]. These drugs have distinct mechanisms of action of inhibiting rRNA synthesis. BMH-21 was initially found as an activator of p53, and was later identified to induce nucleolar stress by inhibiting RNA pol I binding to the rDNA promoter and decreased rRNA synthesis [13, 18]. In contrast, CX-5461 inhibits the interaction among SL1 and rDNA thereby preventing the formation of preinitiation complex. Bywater et al. [10] showed therapeutic potential of CX-5461 therapy in mouse model of melanoma and MLL-AF9 acute myeloid leukemia. Their operate showed that nucleolar stress triggered by CX-5461 selectively led to p53 activation and subsequent bio-THZ1 manufacturer apoptosis in cancer cells. Not too long ago, we’ve shown that CX-5461 arrests acute lymphoblastic leukemia (ALL) cells in G2 phase and induces apoptosis in p53 independent manner [19]. In recent years, potent but transient inhibition of BCR-ABL kinase in CML, and PI3K in breast cancer models has been shown to become an effective therapeutic strategy [20, 21, 22]. Here, we investigated the cellular response to transient inhibition of rRNA synthesis with CX-5461 therapy. We discovered that brief exposure to CX-5461 produces related effects as observed with continuous treatment. Regardless of reactivation of rRNA synthesis activity inside 24 h of drug washout, transient and potent inhibition of rRNA synthesis with CX-5461 was enough to commit ALL cells to irreversible cell death. Aside from acute treatment method, we also investigated rational drug combinations that can enhance the cytotoxicity of continuous CX-5461 therapy. Within this report we analyzed the impact of inhibiting cellular pathways activated by CX-5461 treatment. We showed that checkpoint kinase inhibitor UCN-01 and MAPK pathway inhibitors enhance CX-5461 mediated cytotoxicity.irrevocably induce cell death in ALL cells. Cells were treated with 250 nM CX-5461 or DMSO for 24 hours, washed twice in the culture medium and suspended in drug free medium. We measured cell proliferation applying the colorimetric MTS assay at day 1 and three just after resuspension. All cell lines showed a time dependent reduction in cell proliferation in washout cells relative to manage treated cells (Figure 1A). To assess the extent to which lowered proliferation was resulting from induction of cell death (as opposed to development arrest only), we measured cell death at day 3 after washout applying FACS right after staining with propidium iodide (PI). All cell lines showed important reduction in proportion of reside cells (i.e., PI unfavorable) in washout cells compared to DMSO treated controls just after 3 days (Figure 1B). To investigate if a shorter incubation with CX-5461 would still outcome in cytotoxicity, we exposed the cells to CX-5461 for 3 hours and 5 hours. We measured cell viability using trypan blue 4 days just after washout. All cell lines showed a reduction in viability in drug washout cells (Figure 1C). We then.

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