摘要
3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole(YC-1),the hypoxia-inducible factor-1 alpha(HIF-1α) inhibitor,suppresses tumor proliferation and metastasis by down-regulating HIF-1α expression under hypoxic conditions.Our previous studies demonstrated that YC-1 inhibited breast cancer cell proliferation under normoxic conditions.In the current study,we investigated the targets of YC-1 and mechanism of its action in MDA-MB-468 breast cancer cells.In the in vitro experiments,we found that YC-1 significantly inhibited MDA-MB-468 cell proliferation in normoxia and hypoxia.Under normoxic conditions,YC-1 induced apoptosis of MDA-MB-468 cells and blocked cell cycle in the G1 phase,and these effects were possibly related to caspase 8,p21,and p27 expression.RT-PCR and Western blotting results showed that YC-1 primarily inhibited HIF-1α at the mRNA and protein levels under hypoxic conditions,but suppressed the expression of epidermal growth factor receptor(EGFR) at the mRNA and protein levels under normoxic conditions.In vivo,YC-1 prolonged survival,increased survival rate,decreased tumor size and metastasis rate,and inhibited tissue EGFR and HIF-1α expression.However,YC-1 exerted no obvious effect on body weight.These results indicate that YC-1 inhibits the proliferation of MDA-MB-468 cells by acting on multiple targets with minimal side effects.Thus,YC-1 is a promising target drug for breast cancer.
3-（5＇-hydroxymethyl-2＇-furyl）-l-benzyl indazole （YC-1）, the hypoxia-inducible factor-1 alpha （HIF-1α） inhibitor, suppresses tumor proliferation and metastasis by down-regulating HIF-la expression under hypoxic conditions. Our previous studies demonstrated that YC-1 inhibited breast cancer cell proliferation under normoxic conditions. In the current study, we investigated the targets of YC-1 and mechanism of its action in MDA-MB-468 breast cancer cells. In the in vitro experiments, we found that YC-1 significantly inhibited MDA-MB-468 cell proliferation in normoxia and hypoxia. Under normoxic conditions, YC-1 induced apoptosis of MDA-MB-468 cells and blocked cell cycle in the G1 phase, and these effects were possibly related to caspase 8, p21, and p27 expression. RT-PCR and Western blotting results showed that YC-1 primarily inhibited HIF-1α at the mRNA and protein levels under hypoxic conditions, but suppressed the expression of epidermal growth factor receptor （EGFR） at the mRNA and protein levels under normoxic conditions. In vivo, YC-1 prolonged survival, increased survival rate, decreased tumor size and metastasis rate, and inhibited tissue EGFR and HIF-1α expression. However, YC-1 exerted no obvious effect on body weight. These results indicate that YC-1 inhibits the proliferation of MDA-MB-468 cells by acting on multiple targets with minimal side effects. Thus, YC-1 is a promising target drug for breast cancer.
基金
supported by a grant from Jilin Province Science and Technology Development Project(No.200905198)
