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rRNA synthesis inhibitor, CX-5461, activates ATM/ATR pathway in acute lymphoblastic leukemia, arrests cells in G2 phase and induces apoptosis.
Oncotarget. 2015 Jul 20; 6(20):18094-104.O

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+Show Affiliations

Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26061708

Citation

Negi, Sandeep S., and Patrick Brown. "RRNA Synthesis Inhibitor, CX-5461, Activates ATM/ATR Pathway in Acute Lymphoblastic Leukemia, Arrests Cells in G2 Phase and Induces Apoptosis." Oncotarget, vol. 6, no. 20, 2015, pp. 18094-104.
Negi SS, Brown P. RRNA synthesis inhibitor, CX-5461, activates ATM/ATR pathway in acute lymphoblastic leukemia, arrests cells in G2 phase and induces apoptosis. Oncotarget. 2015;6(20):18094-104.
Negi, S. S., & Brown, P. (2015). RRNA synthesis inhibitor, CX-5461, activates ATM/ATR pathway in acute lymphoblastic leukemia, arrests cells in G2 phase and induces apoptosis. Oncotarget, 6(20), 18094-104.
Negi SS, Brown P. RRNA Synthesis Inhibitor, CX-5461, Activates ATM/ATR Pathway in Acute Lymphoblastic Leukemia, Arrests Cells in G2 Phase and Induces Apoptosis. Oncotarget. 2015 Jul 20;6(20):18094-104. PubMed PMID: 26061708.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - rRNA synthesis inhibitor, CX-5461, activates ATM/ATR pathway in acute lymphoblastic leukemia, arrests cells in G2 phase and induces apoptosis. AU - Negi,Sandeep S, AU - Brown,Patrick, PY - 2015/04/08/received PY - 2015/05/23/accepted PY - 2015/6/11/entrez PY - 2015/6/11/pubmed PY - 2016/5/25/medline KW - ATM/ATR pathway KW - CX-5461 KW - G2/M arrest KW - acute lymphoblastic leukemia KW - rRNA synthesis SP - 18094 EP - 104 JF - Oncotarget JO - Oncotarget VL - 6 IS - 20 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/26061708/rRNA_synthesis_inhibitor_CX_5461_activates_ATM/ATR_pathway_in_acute_lymphoblastic_leukemia_arrests_cells_in_G2_phase_and_induces_apoptosis_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=4093 DB - PRIME DP - Unbound Medicine ER -