title: YC-1 induces S cell cycle arrest and apoptosis by activating checkpoint kinases.
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.
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Yeo
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Ryu
authors.forename: Yang-Sook
authors.initials: YS
authors.lastname: Chun
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Cho
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: HoSung
authors.initials: H
authors.lastname: Cho
authors.forename: Jinho
authors.initials: J
authors.lastname: Kim
authors.forename: Myung-Suk
authors.initials: MS
authors.lastname: Kim
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors; D007191:Indazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects* / Q000502:physiology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D047428:Protein Kinase Inhibitors; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases