S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Physiology (생리학교실) Journal Papers (저널논문_생리학교실)
YC-1 induces S cell cycle arrest and apoptosis by activating checkpoint kinases
- 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
- American Association for Cancer Research
- Cancer Res 2006;66:6345-52
- Apoptosis/*drug effects/physiology; Carcinoma, Hepatocellular/drug therapy/enzymology/pathology; Cell Growth Processes/drug effects; Cell Line, Tumor; Enzyme Activation/drug effects; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors; Indazoles/pharmacokinetics/*pharmacology; Liver Neoplasms/drug therapy/enzymology/pathology; Protein Kinase Inhibitors/pharmacokinetics/pharmacology; Protein Kinases/*metabolism; Protein-Serine-Threonine Kinases/*metabolism; S Phase/*drug effects/physiology
- 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.
- 0008-5472 (Print)
- Files in This Item: There are no files associated with this item.