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YC-1 induces S cell cycle arrest and apoptosis by activating checkpoint kinases

Cited 48 time in Web of Science Cited 50 time in Scopus
Authors
Yeo, Eun-Jin; Ryu, Ji-Hye; Chun, Yang-Sook; Cho, Young-Suk; Jang, In-Jin; Cho, HoSung; Kim, Jinho; Kim, Myung-Suk; Park, Jong-Wan
Issue Date
2006-06-15
Publisher
American Association for Cancer Research
Citation
Cancer Res 2006;66:6345-52
Keywords
Apoptosis/*drug effects/physiologyCarcinoma, Hepatocellular/drug therapy/enzymology/pathologyCell Growth Processes/drug effectsCell Line, TumorEnzyme Activation/drug effectsHumansHypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitorsIndazoles/pharmacokinetics/*pharmacologyLiver Neoplasms/drug therapy/enzymology/pathologyProtein Kinase Inhibitors/pharmacokinetics/pharmacologyProtein Kinases/*metabolismProtein-Serine-Threonine Kinases/*metabolismS Phase/*drug effects/physiology
Abstract
Hypoxia-inducible factor-1alpha (HIF-1alpha) seems central to tumor growth and progression because it up-regulates genes essential for angiogenesis and the hypoxic adaptation of cancer cells, which is why HIF-1alpha inhibition is viewed as a cancer therapy strategy. Paradoxically, HIF-1alpha also leads to cell cycle arrest or the apoptosis of cancer cells. Thus, the possibility cannot be ruled out that HIF-1alpha inhibitors unlock cell cycle arrest under hypoxic conditions and prevent cell death, which would limit the anticancer effect of HIF-1alpha inhibitors. Previously, we reported on the development of YC-1 as an anticancer agent that inhibits HIF-1alpha. In the present study, we evaluated the effects of YC-1 on hypoxia-induced cell cycle arrest and cell death. It was found that YC-1 does not reverse the antiproliferative effect of hypoxia, but rather that it induces S-phase arrest and apoptosis at therapeutic concentrations that inhibit HIF-1alpha and tumor growth; however, YC-1 did not stimulate cyclic guanosine 3',5'-monophosphate production in this concentration range. It was also found that YC-1 activates the checkpoint kinase-mediated intra-S-phase checkpoint, independently of ataxia-telangiectasia mutated kinase or ataxia-telangiectasia mutated and Rad3-related kinase. These results imply that YC-1 does not promote the regrowth of hypoxic tumors because of its cell cycle arrest effect. Furthermore, YC-1 may induce the combined anticancer effects of HIF-1alpha inhibition and cell growth inhibition.
ISSN
0008-5472 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16778212

http://hdl.handle.net/10371/24864
DOI
https://doi.org/10.1158/0008-5472.CAN-05-4460
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Physiology (생리학교실)Journal Papers (저널논문_생리학교실)
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