Targeting breast cancer cells by MRS1477, a positive allosteric modulator of TRPV1 channels

• Published in: PloS one Vol. 12; no. 6; p. e0179950
• Main Authors: Nazıroğlu, Mustafa, Çiğ, Bilal, Blum, Walter, Vizler, Csaba, Buhala, Andrea, Marton, Annamária, Katona, Róbert, Jósvay, Katalin, Schwaller, Beat, Oláh, Zoltán, Pecze, László
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22-06-2017; Public Library of Science (PLoS)
• Subjects: Allosteric properties; Allosteric Regulation - drug effects; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Apoptosis - drug effects; Bearing; Biochemistry; Biology and Life Sciences; Body weight; Breast cancer; Breast Neoplasms - pathology; Calcium Signaling - drug effects; Calcium signalling; Cancer; Cancer cells; Capsaicin; Capsaicin - pharmacology; Capsaicin receptors; Capsazepine; Caspase; Caspase-3; Cell Survival - drug effects; Channels; Current density; Cytotoxicity; Dihydropyridine; Dihydropyridines - pharmacology; Dose-Response Relationship, Drug; Drug Interactions; Epidemiology; Epithelial cells; Humans; Immunodeficiency; Injection; Kinases; MCF-7 Cells; Medical research; Medicine and Health Sciences; Membrane Potential, Mitochondrial - drug effects; Metabolites; Mice; Molecular Targeted Therapy; Neurosciences; Optimization; Oxidative stress; Oxidative Stress - drug effects; Oxygen; Pain; Prostate cancer; Reactive oxygen species; Reactive Oxygen Species - metabolism; Science; Transient receptor potential proteins; TRPV Cation Channels - metabolism; Tumor Microenvironment - drug effects; Tumors; Xenograft Model Antitumor Assays; Hungary; Turkey
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0179950

There is convincing epidemiological and experimental evidence that capsaicin, a potent natural transient receptor potential cation channel vanilloid member 1 (TRPV1) agonist, has anticancer activity. However, capsaicin cannot be given systemically in large doses, because of its induction of acute pain and neurological inflammation. MRS1477, a dihydropyridine derivative acts as a positive allosteric modulator of TRPV1, if added together with capsaicin, but is ineffective, if given alone. Addition of MRS1477 evoked Ca2+ signals in MCF7 breast cancer cells, but not in primary breast epithelial cells. This indicates that MCF7 cells not only express functional TRPV1 channels, but also produce endogenous TRPV1 agonists. We investigated the effects of MRS1477 and capsaicin on cell viability, caspase-3 and -9 activities and reactive oxygen species production in MCF7 cells. The fraction of apoptotic cells was increased after 3 days incubation with capsaicin (10 μM) paralleled by increased reactive oxygen species production and caspase activity. These effects were even more pronounced, when cells were incubated with MRS1477 (2 μM) either alone or together with CAPS (10 μM). Capsazepine, a TRPV1 blocker, inhibited both the effect of capsaicin and MRS1477. Whole-cell patch clamp recordings revealed that capsaicin-evoked TRPV1-mediated current density levels were increased after 3 days incubation with MRS1477 (2 μM). However, the tumor growth in MCF7 tumor-bearing immunodeficient mice was not significantly decreased after treatment with MRS1477 (10 mg/ kg body weight, i.p., injection twice a week). In conclusion, in view of a putative in vivo treatment with MRS1477 or similar compounds further optimization is required.