3. Circadian clock as novel therapeutic strategies for the treatment of glioblastoma

PAULA M. WAGNER; MARIO E. GUIDO; CESAR G PRUCCA; BEATRIZ CAPUTTO

Congreso; LASC; 2021

The circadian system temporally regulates diverse cellular processes in organs, tissues, and even in individual cells, including tumor cells. The potentiality of the function of the circadian clock on cancer cell modulation offers a new target for novel treatments. Here, we investigate a chrono-chemotherapeutic administration of SR9009 (agonists of REV-ERBs) and Bortezomib in different glioma models. First, T98G glioblastoma cultures exhibited a differential temporal susceptibility to SR9009 treatment with the lowest levels of viability during a time window going from 18 to 30 hours after synchronization. Moreover, when Bortezomib and SR9009 were given together at lower doses in T98G cultures, the viability was significantly reduced as compared with each drug alone. On the other hand, in vivo studies evidenced a total tumor growth inhibition (TGI) when Bortezomib was applied at a high dose at the beginning of the day or night in a murine glioma model. On the contrary, at a low dose of Bortezomib, the nocturnal treatment showed a greater effect on tumor volume as compared with daytime treatment exhibiting a TGI of 70% for the night administration and only 18% for the day treatment. Our observations strongly suggest that the chemotherapeutic treatment efficacy is subject to a tight temporal control of the circadian clock. Understanding and delving into tumor regulation from a chronobiological viewpoint will further help to design new treatments that maximize therapeutic benefits at precise day-times.