Circadian Rhythm of Anti-Cancer Drug Target Topoisomerase I As a Proposal Model for Chronotherapy In Vitro

Abstract

Many behavioral processes are under circadian regulation in almost all organisms from bacteria to mammals. Although substantial evidences support the idea that circadian clock could modulate the efficacy of anticancer therapy, the mechanism(s) has not been clear. Here we demonstrated that expression of topoisomerase I (top1) mRNA and its promoter activity underwent circadian oscillation after serum-rich medium treatment in HCT 116 cells. Moreover, the formation of cleavage complex composed of top1 and top1 poison, camptothecin (CPT), detected by nicking assay was also oscillated. Colony formation assay indicated that cytotoxicity of 8h-CPT treatment was significantly higher at 4-h after serum-shock than at 20-h (p = 0.0289). In addition, dexamethasone treatment also induced circadian rhythm of top1 in HCT 116 cells. These results raise the possibility that the circadian rhythm of top1, which would be induced by some types of drugs such as dexamethasone, could be considered for chemotherapy in clinic.