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YC-1 Induces S Cell Cycle Arrest and Apoptosis by Activating Checkpoint Kinases

Departments of ¹ Pharmacology and ² Physiology and Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea; and ³ Technology and Process Development, Ambrx, San Diego, California

Requests for reprints: Jong-Wan Park, Department of Pharmacology, College of Medicine, Seoul National University, 28 Yongon-dong, Chongno-gu, 110-799 Seoul, South Korea. Fax: 82-2-7457996; E-mail: parkjw{at}snu.ac.kr.

Hypoxia-inducible factor-1 (HIF-1) 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-1 inhibition is viewed as a cancer therapy strategy. Paradoxically, HIF-1 also leads to cell cycle arrest or the apoptosis of cancer cells. Thus, the possibility cannot be ruled out that HIF-1 inhibitors unlock cell cycle arrest under hypoxic conditions and prevent cell death, which would limit the anticancer effect of HIF-1 inhibitors. Previously, we reported on the development of YC-1 as an anticancer agent that inhibits HIF-1. 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-1 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-1 inhibition and cell growth inhibition. (Cancer Res 2006; 66(12): 6345-52)

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