Format

Send to

Choose Destination
BMC Complement Altern Med. 2016 Aug 9;16:278. doi: 10.1186/s12906-016-1254-2.

Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis.

Author information

1
Department of Plant Science, The Pennsylvania State University, University Park, PA, 16802, USA.
2
Department of Food Science, The Pennsylvania State University, 326 Food Science Building, University Park, PA, 16803, USA.
3
Department of Biotechnology & Bioinformatics, Yogi Vemana University, Kadapa, Andhra Pradesh, 516216, India.
4
The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, 16802, USA.
5
Department of Food Science, The Pennsylvania State University, 326 Food Science Building, University Park, PA, 16803, USA. juv4@psu.edu.
6
The Pennsylvania State Hershey Cancer Institute, Penn State Milton S. Hershey Medical Center, Hershey, PA, 17033, USA. juv4@psu.edu.
7
Center for Molecular Immunology and Infectious Diseases, The Pennsylvania State University, University Park, PA, 16802, USA. juv4@psu.edu.

Abstract

BACKGROUND:

We have previously shown that the grape bioactive compound resveratrol (RSV) potentiates grape seed extract (GSE)-induced colon cancer cell apoptosis at physiologically relevant concentrations. However, RSV-GSE combination efficacy against colon cancer stem cells (CSCs), which play a key role in chemotherapy and radiation resistance, is not known.

METHODS:

We tested the anti-cancer efficacy of the RSV-GSE against colon CSCs using isolated human colon CSCs in vitro and an azoxymethane-induced mouse model of colon carcinogenesis in vivo.

RESULTS:

RSV-GSE suppressed tumor incidence similar to sulindac, without any gastrointestinal toxicity. Additionally, RSV-GSE treatment reduced the number of crypts containing cells with nuclear β-catenin (an indicator of colon CSCs) via induction of apoptosis. In vitro, RSV-GSE suppressed - proliferation, sphere formation, nuclear translocation of β-catenin (a critical regulator of CSC proliferation) similar to sulindac in isolated human colon CSCs. RSV-GSE, but not sulindac, suppressed downstream protein levels of Wnt/β-catenin pathway, c-Myc and cyclin D1. RSV-GSE also induced mitochondrial-mediated apoptosis in colon CSCs characterized by elevated p53, Bax/Bcl-2 ratio and cleaved PARP. Furthermore, shRNA-mediated knockdown of p53, a tumor suppressor gene, in colon CSCs did not alter efficacy of RSV-GSE.

CONCLUSION:

The suppression of Wnt/β-catenin signaling and elevated mitochondrial-mediated apoptosis in colon CSCs support potential clinical testing/application of grape bioactives for colon cancer prevention and/or therapy.

KEYWORDS:

Chemoprevention; Colon cancer stem cells; Grape seed extract; Resveratrol; β-catenin

PMID:
27506388
PMCID:
PMC4977641
DOI:
10.1186/s12906-016-1254-2
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

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