title: Molecular mechanisms for inhibition of colon cancer cells by combined epigenetic-modulating epigallocatechin gallate and sodium butyrate.
abstract: Bioactive compounds are considered safe and have been shown to alter genetic and epigenetic profiles of tumor cells. However, many of these changes have been reported at molecular concentrations higher than physiologically achievable levels. We investigated the role of the combinatorial effects of epigallocatechin gallate (EGCG), a predominant polyphenol in green tea, and sodium butyrate (NaB), a dietary microbial fermentation product of fiber, in the regulation of survivin, which is an overexpressed anti-apoptotic protein in colon cancer cells. For the first time, our study showed that the combination treatment induced apoptosis and cell cycle arrest in RKO, HCT-116 and HT-29 colorectal cancer cells. This was found to be regulated by the decrease in HDAC1, DNMT1, survivin and HDAC activity in all three cell lines. A G2/M arrest was observed for RKO and HCT-116 cells, and G1 arrest for HT-29 colorectal cancer cells for combinatorial treatment. Further experimentation of the molecular mechanisms in RKO colorectal cancer (CRC) cells revealed a p53-dependent induction of p21 and an increase in nuclear factor kappa B (NF-κB)-p65. An increase in double strand breaks as determined by gamma-H2A histone family member X (γ-H2AX) protein levels and induction of histone H3 hyperacetylation was also observed with the combination treatment. Further, we observed a decrease in global CpG methylation. Taken together, these findings suggest that at low and physiologically achievable concentrations, combinatorial EGCG and NaB are effective in promoting apoptosis, inducing cell cycle arrest and DNA-damage in CRC cells.
authors: Department of Biology, University of Alabama at Birmingham, 175 Campbell Hall, 1300 University Boulevard, Birmingham, AL 35294, USA; Department of Biological Sciences, Alabama State University, Montgomery, AL 36104, USA. Electronic address: sabivan@uab.edu.
authors: Sabita N
authors: SN
authors: Saldanha
authors: Department of Biology, University of Alabama at Birmingham, 175 Campbell Hall, 1300 University Boulevard, Birmingham, AL 35294, USA.
authors: Rishabh
authors: R
authors: Kala
authors: Department of Biology, University of Alabama at Birmingham, 175 Campbell Hall, 1300 University Boulevard, Birmingham, AL 35294, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Comprehensive Center for Healthy Aging, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Comprehensive Diabetes Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: trygve@uab.edu.
authors: Trygve O
authors: TO
authors: Tollefsbol
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020148:Butyric Acid / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D020148:Butyric Acid; D002392:Catechin; C045651:epigallocatechin gallate
keywords: Colon cancer; Epigallocatechine gallate; Epigenetics; Histone deacetylases; Methylation; Sodium butyrate