Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Reddivari, Lavanya; Charepalli, Venkata; Radhakrishnan, Sridhar; Vadde, Ramakrishna; Elias, Ryan; Lambert, Joshua; Vanamala, Jairam
• Is Part Of: BMC complementary and alternative medicine. Volume 16:Issue 1(2016)
• Page Start: 1
• Page End: 12
• Publication Date: 2016-12
• Subjects: Colon cancer stem cells -- Resveratrol -- Grape seed extract -- β-catenin -- Chemoprevention; Alternative medicine -- Periodicals; Complementary Therapies -- Periodicals; 615.505
• DOI: 10.1186/s12906-016-1254-2
• Languages: English
• ISSNs: 1472-6882

Abstract

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.