title: rRNA synthesis inhibitor, CX-5461, activates ATM/ATR pathway in acute lymphoblastic leukemia, arrests cells in G2 phase and induces apoptosis.
abstract: Ribosome biogenesis is a fundamental cellular process and is elevated in cancer cells. As one of the most energy consuming cellular processes, it is highly regulated by signaling pathways in response to changing cellular conditions. Many of the regulators of this process are aberrantly activated in various cancers. Recently two novel rRNA synthesis inhibitors, CX-5461 and BMH-21, have been shown to selectively kill cancer cells while sparing normal cells. Here, we tested the effectiveness of pre-rRNA synthesis inhibitor CX-5461 on acute lymphoblastic leukemia cells with different cytogenetic abnormalities. Acute lymphoblastic leukemia cells are more sensitive to rRNA synthesis inhibition compared to normal bone marrow cells. CX-5461 treated cells undergo caspase-dependent apoptosis independent of their p53 status. More-over, CX5461, activates checkpoint kinases and arrests cells in G2 phase of cell cycle. Finally, overcoming this G2 arrest by inhibiting ATR kinase leads to robust cell killing. These results show that CX-5461 can be even more potent in combination with ATR inhibitors.
authors.affiliation: Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Negi
authors.affiliation: Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Brown
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D052160:Benzothiazoles / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D009287:Naphthyridines / Q000494:pharmacology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012318:RNA Polymerase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012335:RNA, Ribosomal / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; C557717:CX 5461; D009287:Naphthyridines; D019384:Nucleic Acid Synthesis Inhibitors; D047428:Protein Kinase Inhibitors; D012335:RNA, Ribosomal; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D012318:RNA Polymerase I; D020169:Caspases
keywords: ATM/ATR pathway; CX-5461; G2/M arrest; acute lymphoblastic leukemia; rRNA synthesis