Investigation of Novel Small Molecular TRPM4 Inhibitors in Colorectal Cancer Cells
Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland
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Author to whom correspondence should be addressed.
Cancers 2021, 13(21), 5400; https://doi.org/10.3390/cancers13215400
Submission received: 25 August 2021
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Revised: 21 October 2021
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Accepted: 26 October 2021
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Published: 28 October 2021
(This article belongs to the Collection Ion Channels in Cancer Therapies)
Simple Summary
Transient receptor potential melastatin 4 (TRPM4) ion channel malfunction or aberrant expression is implicated in many diseases, including different cancers and cardiovascular diseases. Currently, there is a need for specific and potent TRPM4 inhibitors. They would allow to study the role of TRPM4 in disease models and to validate it as a potential target in therapies, including anti-cancer therapy. In colorectal cancer (CRC), TRPM4 is upregulated, and its conductivity plays a role in the regulation of viability and cell cycle of CRC cells. In this study, we tested three novel TRPM4 inhibitors, CBA, NBA, and LBA, in CRC cells. In HCT116 cells, we show that NBA inhibits TRPM4 currents in the micromolar range and alters proliferation and cell cycle. Furthermore, NBA decreases the viability of Colo205 cells. This makes NBA a promising candidate for further evaluation as a specific TRPM4 inhibitor in other cellular systems and disease models.
Abstract
(1) Background: Transient receptor potential melastatin (TRPM4) ion channel aberrant expression or malfunction contributes to different types of cancer, including colorectal cancer (CRC). However, TRPM4 still needs to be validated as a potential target in anti-cancer therapy. Currently, the lack of potent and selective TRPM4 inhibitors limits further studies on TRPM4 in cancer disease models. In this study, we validated novel TRPM4 inhibitors, CBA, NBA, and LBA, in CRC cells. (2) Methods: The potency to inhibit TRPM4 conductivity in CRC cells was assessed with the whole-cell patch clamp technique. Furthermore, the impact of TRPM4 inhibitors on cellular functions, such as viability, proliferation, and cell cycle, were assessed in cellular assays. (3) Results: We show that in CRC cells, novel TRPM4 inhibitors irreversibly block TRPM4 currents in a low micromolar range. NBA decreases proliferation and alters the cell cycle in HCT116 cells. Furthermore, NBA reduces the viability of the Colo205 cell line, which highly expresses TRPM4. (4) Conclusions: NBA is a promising new TRPM4 inhibitor candidate, which could be used to study the role of TRPM4 in cancer disease models and other diseases.
Keywords:
TRPM4; ion channels; small molecule inhibitors; patch clamp
