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

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.

• Authors: Lavanya Reddivari, Venkata Charepalli, Sridhar Radhakrishnan, Ramakrishna Vadde, Ryan J Elias, Joshua D Lambert, Jairam K P Vanamala
• Journal: BMC complementary and alternative medicine (BMC Complement Altern Med) Vol. 16 Pg. 278 (Aug 09 2016) ISSN: 1472-6882 [Electronic] England
• PMID: 27506388 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Phytogenic
• Grape Seed Extract
• Stilbenes
• beta Catenin
• Resveratrol

Topics

• Animals
• Antineoplastic Agents, Phytogenic (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Colonic Neoplasms (metabolism, pathology)
• Disease Models, Animal
• Grape Seed Extract (chemistry, pharmacology)
• Male
• Mice
• Neoplastic Stem Cells (drug effects, metabolism)
• Resveratrol
• Signal Transduction (drug effects)
• Stilbenes (chemistry, pharmacology)
• Vitis (chemistry)
• beta Catenin (metabolism)