Bortezomib alters sour taste sensitivity in mice

Abstract

Chemotherapy-induced taste disorder is one of the critical issues in cancer therapy. Bortezomib, a proteasome inhibitor, is a key agent in multiple myeloma therapy, but it induces a taste disorder. In this study, we investigated the characteristics of bortezomib-induced taste disorder and the underlying mechanism in mice. Among the five basic tastes, the sour taste sensitivity of mice was significantly increased by bortezomib administration. In bortezomib-administered mice, protein expression of PKD2L1 was increased. The increased sour taste sensitivity induced by bortezomib returned to the control level on cessation of its administration. These results suggest that an increase in protein expression of PKD2L1 enhances the sour taste sensitivity in bortezomib-administered mice, and this alteration is reversed on cessation of its administration.

Keywords: AADC, aromatic amino acid decarboxylase; Adverse effect; BSA, bovine serum albumin; Bortezomib; CP, circumvallate papillae; Chemotherapy; DMSO, dimethyl sulfoxide; HCl, hydrochloric acid; HE, hematoxylin-eosin; MSG, mono sodium glutamate; NaCl, sodium chloride; QHCl, quinine hydrochloride; Sour taste; Taste disorder.

Fig. 1

Behavioral responses to five basic taste solutions in bortezomib-administered mice. The lick ratios for 300 and 50 mM sucrose with 0.3 mM QHCl (A, B), 5 and 10 mM citric acid (C, D), 0.3 and 1 mM QHCl (E, F), 150 and 500 mM NaCl (G, H), and 300 and 50 mM MSG with 0.3 mM QHCl and 30 μM amiloride (I, J) were determined in control and bortezomib-administered mice on days 0 (Base), 2, 5, 9, 12, 16, 19, 23 and 26. Each bar represents the mean ± SD (N = 4–10). *: p <0.05 vs control in multiple comparison of Bonferroni test.

Fig. 2

Behavioral responses to citric acid solutions in bortezomib-administered mice. The lick ratios for 5–100 mM citric acid (A–I) were determined in control and bortezomib-administered mice on days 0 (Base), 2, 5, 9, 12, 16, 19, 23 and 26. Concentrations of citric acid solutions were 5, 10, 30 and 100 mM. Each point represents the mean ± SD (N = 4–9). *: p <0.05 vs control in multiple comparison of Bonferroni test. BTZ: bortezomib.

Fig. 3

Behavioral responses to HCl solutions in bortezomib-administered mice. The lick ratios for 3.2–32 mM HCl (A–I) were determined in control and bortezomib-administered mice on day 0 (Base), 2, 5, 9, 12, 16, 19, 23 and 26. Concentrations of HCl solutions were 3.2, 10, 16 and 32 mM. Each point represents the mean ± SD (N = 4–10). *: p < 0.05 vs control in multiple comparison of Bonferroni test. BTZ: bortezomib.

Fig. 4

Expression levels of PKD1L3 and PKD2L1 in the CP of bortezomib-administered mice. (A) Quantification of the mRNA expression of PKD1L3 and PKD2L1 in the CP of control and bortezomib-administered mice on day 26 was performed by real-time PCR. Each bar represents the mean ± SD (N = 5 − 7). Panel B shows representative immunohistochemical images for PKD2L1 (green) and Car4 (red), the quantitative results for PKD2L1 and Car4-fluorescent intensity in CP being given in panel C. Scale bar = 100 μm. Each bar represents the mean ± SD (N = 5). *: p < 0.05 vs control. BTZ: bortezomib.

Fig. 5

Behavioral response to citric acid solutions after the cessation of multiple bortezomib administration in mice. Mice were administered bortezomib or the vehicle following the schedule described under Materials and Methods up to day 36, and a brief-access test with 5, 10, 30 and 100 mM citric acid solutions was performed on day 30, and 3, 7 and 10 days after the final bortezomib administration. Each point represents the mean ± SD (N = 5–7). *: p < 0.05 vs control in multiple comparison of Bonferroni test. BTZ: bortezomib.