title: Inhibitors of glutamate release from breast cancer cells; new targets for cancer-induced bone-pain.
abstract: Glutamate is an important signaling molecule in a wide variety of tissues. Aberrant glutamatergic signaling disrupts normal tissue homeostasis and induces several disruptive pathological conditions including pain. Breast cancer cells secrete high levels of glutamate and often metastasize to bone. Exogenous glutamate can disrupt normal bone turnover and may be responsible for cancer-induced bone pain (CIBP). CIBP is a significant co-morbidity that affects quality of life for many advanced-stage breast cancer patients. Current treatment options are commonly accompanied by serious side-effects that negatively impact patient care. Identifying small molecule inhibitors of glutamate release from aggressive breast cancer cells advances a novel, mechanistic approach to targeting CIBP that could advance treatment for several pathological conditions. Using high-throughput screening, we investigated the ability of approximately 30,000 compounds from the Canadian Compound Collection to reduce glutamate release from MDA-MB-231 breast cancer cells. This line is known to secrete high levels of glutamate and has been demonstrated to induce CIBP by this mechanism. Positive chemical hits were based on the potency of each molecule relative to a known pharmacological inhibitor of glutamate release, sulfasalazine. Efficacy was confirmed and drug-like molecules were identified as potent inhibitors of glutamate secretion from MDA-MB-231, MCF-7 and Mat-Ly-Lu cells.
authors: Michael G. DeGroote Institute for Pain Research and Care, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario Canada.
authors: Jennifer
authors: J
authors: Fazzari
authors: Michael G. DeGroote Institute for Pain Research and Care, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario Canada.
authors: Hanxin
authors: H
authors: Lin
authors: Centre for Microbial Chemical Biology, McMaster University, Hamilton, Ontario Canada.
authors: Cecilia
authors: C
authors: Murphy
authors: Michael G. DeGroote Institute for Pain Research and Care, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario Canada.
authors: Robert
authors: R
authors: Ungard
authors: Michael G. DeGroote Institute for Pain Research and Care, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario Canada.
authors: Gurmit
authors: G
authors: Singh
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000150:complications / Q000378:metabolism*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D018491:Dopamine Agonists / Q000494:pharmacology; D055808:Drug Discovery; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries
chemical_list: D018491:Dopamine Agonists; D054852:Small Molecule Libraries; D018698:Glutamic Acid; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C071423:capsazepine; D002211:Capsaicin