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Life Sci. 2018 Jan 15;193:9-19. doi: 10.1016/j.lfs.2017.11.045. Epub 2017 Nov 28.

Centchroman regulates breast cancer angiogenesis via inhibition of HIF-1α/VEGFR2 signalling axis.

Author information

1
Genotoxicity Lab, Division of Toxicology & Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India.
2
Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India.
3
Genotoxicity Lab, Division of Toxicology & Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India. Electronic address: skrath@cdri.res.in.
4
Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India. Electronic address: anilbalapure58@gmail.com.

Abstract

AIMS:

Angiogenesis is a recognized hallmark of cancer which promotes cancer cell progression and metastasis. Inhibition of angiogenesis to attenuate cancer growth is becoming desirable strategy for breast cancer management. The present study is aimed to investigate the antiangiogenic efficacy of a novel selective estrogen receptor modulator Centchroman (CC) on human breast cancer cells.

MAIN METHODS:

Effect of CC on cell viability was evaluated using Sulforhodamine B assay. Endothelial cell proliferation, wound healing, Boyden chamber cell invasion, tube formation and chorioallantoic membrane (CAM) assays were performed to assess the effect of CC on migration, invasion and angiogenesis. Apoptosis, reactive oxygen species generation, caspase-3/7 and intracellular calcium ion level were measured through flow cytometry. Expression levels of HIF-1α, VEGF, VEGFR2, AKT and ERK were assessed by western blot analysis.

KEY FINDINGS:

CC selectively induces apoptosis in human breast cancer cells without affecting non-tumorigenic breast epithelial cells MCF-10A. Moreover, it inhibits migratory, invasive and mammosphere forming potential of breast cancer. Furthermore, CC also inhibited VEGF-induced migration, invasion and tube formation of HUVECs in vitro. CC effectively inhibited neovasculature formation in chicken CAM. Western blot analysis demonstrated that CC inhibited expression of HIF-1α and its downstream target VEGF. Interestingly, CC also suppressed VEGFR2 phosphorylation and consequently attenuated AKT and ERK phosphorylation.

SIGNIFICANCE:

Our findings suggest that CC downregulates VEGF-induced angiogenesis by modulating HIF-1α/VEGFR2 pathway and recommend it (CC) as a potential therapeutic drug for breast cancer treatment.

KEYWORDS:

Angiogenesis; Breast cancer; Centchroman; Hypoxia-inducible factor 1 α; Ormeloxifene; Vascular endothelial growth factor

PMID:
29196053
DOI:
10.1016/j.lfs.2017.11.045
[Indexed for MEDLINE]

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