Diurnal variations of neurokinin-1 receptor defines dosing time-dependent differences in antitumor effects of aprepitant in mice

Aprepitant, a neurokinin-1 receptor (NK1R) antagonist, has the potential as a novel anticancer agent. This study explored the impact of chronotherapy on the antitumor effect of aprepitant in a mouse model of colorectal carcinoma. Aprepitant inhibited the proliferation of Colon-26 cells in vitro in a concentration-dependent manner and reduced the expression of cell cycle-related genes. Diurnal variations in NK1R mRNA and protein levels were observed in Colon-26 tumors, peaking at zeitgeber time (ZT) 2 and ZT 10, respectively. Administration of aprepitant at ZT 6, achieving peak plasma concentration at ZT 10, significantly reduced the tumor volume compared with administration at ZT 18. Despite the lower plasma concentrations and AUC_0–12 h in the ZT 6 group, superior antitumor effect suggests a dosing time-dependent efficacy due to variations in NK1R expression rather than its pharmacokinetics. These findings indicate that the antitumor activity of aprepitant against colorectal cancer can be enhanced by aligning its administration with NK1R expression rhythms, warranting further exploration of aprepitant chronotherapy in cancer chemotherapy.