YC-1 exerts inhibitory effects on MDA-MB-468 breast cancer cells by targeting EGFR in vitro and in vivo under normoxic condition.
- Author:
Ying CHENG
1
;
Wei LI
;
Ying LIU
;
Huan-Chen CHENG
;
Jun MA
;
Lin QIU
Author Information
- Publication Type:Journal Article
- MeSH: Animals; Antineoplastic Agents; pharmacology; Apoptosis; drug effects; Breast Neoplasms; metabolism; pathology; Cell Cycle; drug effects; Cell Line, Tumor; Cell Proliferation; drug effects; Female; G1 Phase; drug effects; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; antagonists & inhibitors; genetics; metabolism; Indazoles; pharmacology; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Oxygen; metabolism; pharmacology; RNA, Messenger; metabolism; Receptor, Epidermal Growth Factor; genetics; metabolism; STAT3 Transcription Factor; metabolism; Tumor Burden; drug effects
- From:Chinese Journal of Cancer 2012;31(5):248-256
- CountryChina
- Language:English
- Abstract: 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.
