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

Abstract

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)

BRCA1 tumours correlate with a HIF-1α phenotype and have a poor prognosis through modulation of hydroxylase enzyme profile expression

“…Of particular interest include agents targeting FIH because, unlike the prolyl hydroxlases, it retains its activity across a wide range of oxygen tensions (Stolze et al, 2004;Dayan et al, 2006). This is supported by studies suggesting hypoxic tumours may respond to Bortezomib (Shin et al, 2008) and Amphotericin B (Yeo et al, 2006), which suppress HIF-1a activity by re-enforcing FIH-mediated inhibition of p300 recruitment.…”

Treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the effect of radiation therapy

“…It was reported earlier that YC-1 suppresses HIF-1a accumulation through the inhibition of various signalling pathways, including PI3K/Akt/mTOR/4E-BP and NF-kappaB (Sun et al, 2007). In addition, YC-1 is known to have an interesting property arresting cell cycle at S phase and inducing apoptosis in hypoxic cells (Yeo et al, 2006). The difference in the therapeutic effect of three treatment regimens therefore may depend on such YC-1 properties as well as on the 'oxygen effect theory'.…”

CITED2 mediates the paradoxical responses of HIF-1α to proteasome inhibition

“…Primers were designed as previously described (Chun et al, 2002). (b) Luciferase plasmid (0.5 mg) containing erythropoietin (EPO) enhancer or vascular endothelial growth factor (VEGF) promoter was co-transfected with 0.5 mg of b-gal plasmid into Hep3B cells (Yeo et al, 2006). After 16 h incubation, luciferase activities were measured using a Biocounter M1500 luminometer (Lumac) and were normalized to b-gal activity.…”

“…(c) Gal4-CAD (aa. 776-826) (WT) or Gal4-CAD N803A plasmid (1 mg) was co-transfected with Gal4-luc reporter plasmid (1 mg) into HEK293 cells (Yeo et al, 2006). Results (means ± s.d, n ¼ 8) are presented as relative values vs the normoxic control of Gal4-CAD(WT) reporter.…”