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

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