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.
Highlights
Glutamate is an important signaling molecule in a wide variety of tissues
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
high-throughput screening (HTS) allows for the identification of new agents that target glutamate release from aggressive, metastatic cancer cell lines that we have previously shown to release glutamate and one of which was used to induce a cancer-induced bone pain state[46]
Summary
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. 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. Investigating the effects of tumour-secreted factors on the host microenvironment, such as the bone, will provide insights into the physiological mechanisms underlying CIBP This will aid in the development of novel pharmacological strategies for targeted pain interventions. Glutamate is both an ubiquitous cell-signaling molecule in many tissues and a well-characterized excitatory neurotransmitter in the central nervous system (CNS), where it is involved in nociception and pain sensitization[7,8]. Classified as a non-essential amino acid, an exogenous glutamine supply becomes essential for cancer cell metabolism and survival
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