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- Title
Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis.
- Authors
Reddivari, Lavanya; Charepalli, Venkata; Radhakrishnan, Sridhar; Vadde, Ramakrishna; Elias, Ryan J.; Lambert, Joshua D.; Vanamala, Jairam K. P.
- 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.
- Subjects
TISSUE analysis; ANIMAL experimentation; APOPTOSIS; CELL physiology; CELLULAR signal transduction; COLON (Anatomy); COLON tumors; CYTOCHEMISTRY; CYTOSKELETAL proteins; FLUORESCENT antibody technique; GLYCOPROTEINS; MICE; PROBABILITY theory; RESEARCH funding; STATISTICS; STEM cells; SULINDAC; WESTERN immunoblotting; DATA analysis; RESVERATROL; CONTROL groups; DATA analysis software; DESCRIPTIVE statistics; IN vitro studies; GRAPE seed extract; ONE-way analysis of variance; PHARMACODYNAMICS
- Publication
BMC Complementary & Alternative Medicine, 2016, Vol 16, p1
- ISSN
1472-6882
- Publication type
Article
- DOI
10.1186/s12906-016-1254-2