title: 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.
  
  
  CONCLUSIONS
  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: Department of Plant Science, The Pennsylvania State University, University Park, PA, 16802, USA.
authors: Lavanya
authors: L
authors: Reddivari
authors: Department of Food Science, The Pennsylvania State University, 326 Food Science Building, University Park, PA, 16803, USA.
authors: Venkata
authors: V
authors: Charepalli
authors: Department of Food Science, The Pennsylvania State University, 326 Food Science Building, University Park, PA, 16803, USA.
authors: Sridhar
authors: S
authors: Radhakrishnan
authors: Department of Food Science, The Pennsylvania State University, 326 Food Science Building, University Park, PA, 16803, USA.|Department of Biotechnology & Bioinformatics, Yogi Vemana University, Kadapa, Andhra Pradesh, 516216, India.
authors: Ramakrishna
authors: R
authors: Vadde
authors: Department of Food Science, The Pennsylvania State University, 326 Food Science Building, University Park, PA, 16803, USA.
authors: Ryan J
authors: RJ
authors: Elias
authors: Department of Food Science, The Pennsylvania State University, 326 Food Science Building, University Park, PA, 16803, USA.|The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, 16802, USA.
authors: Joshua D
authors: JD
authors: Lambert
authors: Department of Food Science, The Pennsylvania State University, 326 Food Science Building, University Park, PA, 16803, USA. juv4@psu.edu.|The Pennsylvania State Hershey Cancer Institute, Penn State Milton S. Hershey Medical Center, Hershey, PA, 17033, USA. juv4@psu.edu.|Center for Molecular Immunology and Infectious Diseases, The Pennsylvania State University, University Park, PA, 16802, USA. juv4@psu.edu.
authors: Jairam K P
authors: http://orcid.org/0000-0001-6107-9152
authors: JK
authors: Vanamala
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D056604:Grape Seed Extract / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology; D027843:Vitis / Q000737:chemistry*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D056604:Grape Seed Extract; D013267:Stilbenes; D051176:beta Catenin; D000077185:Resveratrol
keywords: Chemoprevention; Colon cancer stem cells; Grape seed extract; Resveratrol; β-catenin