Chemosensory response to Pt-based chemotherapeutics via bitter taste receptors in vitro reveals a new mechanism for bitter taste disorders

Abstract

Abstract Chemotherapeutics like platinum (Pt)-based drugs cause bitter taste disorders, which impair patients’ food intake and quality of life. However, the role of bitter taste receptors (TAS2Rs) remains unexplored, limiting the development of targeted treatments for this clinically impactful side effect. By performing a TAS2R-sensitive bitterness assay based on human gastric parietal cells (HGT-1), we evaluated the bitterness of Pt-based agents and the counteracting potential of the bitter-masking sodium salt of the flavanone homoeriodictyol (Na-HED). Here, we report that carboplatin (50–750 µM) and cisplatin (5–50 µM) elicited dose-dependent cellular bitter responses, with cisplatin evoking a stronger effect. Functional involvement of TAS2R4 and TAS2R5 was confirmed by CRISPR-Cas9 knockout- and siRNA knockdown-experiments. Na-HED reduced the cellular bitter response of 200 µM carboplatin (− 76% ± 11%) and 50 µM cisplatin (– 75% ± 15%). Additionally, this study provides evidence that TAS2Rs modulate the cellular uptake of cytotoxic Pt-based agents, underlining the importance of these chemoreceptors at the cellular level. In conclusion, our results demonstrate a functional role of TAS2Rs in the bitter response induced by Pt-based agents and a counteracting potential of Na-HED, suggesting the development of TAS2R-targeted treatment strategies to address chemotherapy-induced bitter taste hypersensitivity and bitter phantogeusia.