title: In vitro mechanism of action for the cytotoxicity elicited by the combination of epigallocatechin gallate and raloxifene in MDA-MB-231 cells.
abstract: The anticancer effects elicited by epigallocatechin gallate (EGCG) are well established in various models of cancer, while raloxifene is as an established selective estrogen receptor modulator (SERM), which is not yet clinically utilized for the treatment of breast cancer. Previous study from this laboratory has demonstrated that the combination of EGCG (25 microM) and raloxifene (4 microM) elicits a strong cytotoxic response in MDA-MB-231 human breast cancer cells, which lack the estrogen receptor (ER) and erbB-2/ Her-2 receptor. This study was therefore designed to probe the mechanism underlying this cytotoxic response, with an emphasis on determining how the combination treatment influenced the total expression and phosphorylation of key signaling proteins. Specifically, following 12 and 18 h of the combination treatment, we observed significant decreases in the phosphorylation of the epidermal growth factor receptor (EGFR), AKT, mammalian target of rapamycin (mTOR) and S-6-kinase (S6K), and significant increases in the phosphorylation of stress activated protein kinases (SAPKs). Furthermore, these changes were associated with a reduction in the nuclear localization of p65, a major subunit of NF-kappaB. These results demonstrate that the combination of EGCG and raloxifene effectively reduced the mitogenic and survival signaling in MDA-MB-231 cells. Thus, this combination warrants further experimentation as a potential treatment for ER-negative breast cancer.
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Stuart
authors.forename: Reagan M
authors.initials: RM
authors.lastname: Jarvis
authors.forename: Rhonda J
authors.initials: RJ
authors.lastname: Rosengren
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000172:deficiency; D005260:Female; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D002392:Catechin; D066246:ErbB Receptors; D047628:Estrogen Receptor alpha; D020928:Mitogen-Activated Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D020849:Raloxifene Hydrochloride; D018719:Erb-b2 Receptor Tyrosine Kinases; D019893:Ribosomal Protein S6 Kinases; D020845:Selective Estrogen Receptor Modulators; D058570:TOR Serine-Threonine Kinases; D051996:Transcription Factor RelA; C498143:RELA protein, human; C045651:epigallocatechin gallate; C546842:MTOR protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human