capsazepine and Breast-Neoplasms

As canine mammary tumours (CMT) and human breast cancer share clinical and prognostic features, the former have been proposed as a model to study carcinogenesis and improved therapeutic treatment in human breast cancer. In recent years, it has been shown that transient receptor potential vanilloid 1 (TRPV1) is expressed in different neoplastic tissues and its activation has been associated with regulation of cancer growth and progression. The aim of the present research was to demonstrate the presence of TRPV1 in human and canine mammary cancer cells, MCF-7 and CF.41, respectively, and to study the role of TRPV1 in regulating cell proliferation. The images obtained by Western blot showed a signal at 100 kDa corresponding to the molecular weight of TRPV1 receptor. All tested TRPV1 agonists and antagonists caused a significant decrease (P < 0.05) of cell growth rate in MCF-7 cells. By contrast, in CF.41 cells capsaicin and capsazepine induced a significant increase (P < 0.05) in cell proliferation, whereas resiniferatoxin (RTX) and 5-iodo-resiniferatoxin (5-I-RTX) had no influence on CF.41 cell proliferation. Further studies are needed to elucidate the underlying molecular mechanism responsible for the different effects evoked by TRPV1 activation in MCF-7 and CF.41 cells.

Topics: Adenocarcinoma; Animals; Breast Neoplasms; Capsaicin; Cell Line, Tumor; Cell Proliferation; Diterpenes; Dogs; Female; Gene Expression Regulation, Neoplastic; Humans; Mammary Neoplasms, Animal; MCF-7 Cells; TRPV Cation Channels

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.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Bone and Bones; Breast Neoplasms; Capsaicin; Cell Line, Tumor; Dopamine Agonists; Drug Discovery; Female; Glutamic Acid; High-Throughput Screening Assays; Humans; Inhibitory Concentration 50; Pain; Signal Transduction; Small Molecule Libraries