Format

Send to

Choose Destination
J Exp Clin Cancer Res. 2018 Oct 12;37(1):248. doi: 10.1186/s13046-018-0926-9.

Andrographolide inhibits breast cancer through suppressing COX-2 expression and angiogenesis via inactivation of p300 signaling and VEGF pathway.

Peng Y1, Wang Y1, Tang N1,2, Sun D1, Lan Y1, Yu Z1,3, Zhao X1, Feng L1,3, Zhang B1, Jin L1, Yu F3, Ma X4,5, Lv C6.

Author information

1
Institute of Integrative Medicine, College of Pharmacy, College of Basic Medical Science, Dalian Medical University, Dalian, 116044, China.
2
Department of Integrative Medicine, Liaoning University of Traditional Chinese Medicine Xinglin College, Shenyang, 110167, China.
3
Emergency Department, The Second Affiliated Hospital of Hainan Medical University, Haikou, 571199, China.
4
Institute of Integrative Medicine, College of Pharmacy, College of Basic Medical Science, Dalian Medical University, Dalian, 116044, China. maxc1978@163.com.
5
Emergency Department, The Second Affiliated Hospital of Hainan Medical University, Haikou, 571199, China. maxc1978@163.com.
6
Emergency Department, The Second Affiliated Hospital of Hainan Medical University, Haikou, 571199, China. lvchuanzhu677@126.com.

Abstract

BACKGROUND:

Andrographolide (Andro), a diterpenoid lactone, has been used for treatment of various cancers with less adverse effects. However, the underlying mechanisms regarding its anti-tumor mechanism still remain unclear.

METHODS:

Cell viability and proliferation were measured by CCK8 and CFSE dilution assay. The localization of p50/p65 or cytochrome c was determined using confocal immunofluorescence. Streptavidin-agarose pulldown or ChIP assays were used to detect the binding of multiple transactivators to COX-2 promoter. The promoter activity was examined by a dual-Luciferase reporter assay. The functions of Andro on COX-2-mediated angiogenesis were also investigated using human HUVEC cells through tube formation and spheroids sprouting assay. The in vivo anti-tumor efficacy of Andro was analyzed in xenografts nude mice.

RESULTS:

The results indicated that Andro could significantly inhibit the proliferation of human breast cancers, and suppress COX-2 expression at both protein and mRNA levels. Furthermore, Andro could dose-dependently inhibit COX-2-mediated angiogenesis in human endothelial cells. We have also found that Andro significantly promoted the activation of cytochrome c and activated caspase-dependent apoptotic signaling pathway. Our further explorations demonstrated that Andro inhibited the binding of the transactivators CREB2, C-Fos and NF-κB and blocked the recruitment of coactivator p300 to COX-2 promoter. Moreover, Andro could effectively inhibit the activity of p300 histone acetyltransferase (HAT), thereby attenuating the p300-mediated acetylation of NF-κB. Besides, Andro could also dramatically inhibit the migration, invasion and tubulogenesis of HUVECs in vitro. In addition, Andro also exhibited effective anti-tumor efficacy as well as angiogenesis inhibition in vivo.

CONCLUSION:

In current study, we explore the potential effects of Andro in suppressing breast cancer growth and tumor angiogenesis, as well as the precise mechanisms. This work demonstrated the potential anti-cancer effects of Andro, indicating that Andro could inhibit COX-2 expression through attenuating p300 HAT activity and suppress angiogenesis via VEGF pathway, and thereby could be developed as an antitumor agent for the treatment of breast cancer.

KEYWORDS:

Andrographolide; Angiogenesis; Breast cancer; COX-2/NF-κB; p300

PMID:
30314513
PMCID:
PMC6186120
DOI:
10.1186/s13046-018-0926-9
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center