Temporal regulation of tumor growth in nocturnal mammals: In vivo studies and chemotherapeutical potential

Abstract

Tumors of the nervous system including glioblastoma multiforme (GBM) are the most frequent and aggressive form of brain tumors; however, little is known about the impact of the circadian timing system on the formation, growth, and treatment of these tumors. We investigated day/night differences in tumor growth after injection of A530 glioma cells isolated from malignant peripheral nerve sheath tumor (MPNSTs) of NPcis (Trp53 +/− ; Nf1 +/− ) mice. Synchronized A530 cell cultures expressing typical glial markers were injected at the beginning of the day or night into the sciatic nerve zone of C57BL/6 mice subject to a 12:12 hours light/dark (LD) cycle or after being released to constant darkness (DD). Tumors generated in animals injected early at night in the LD cycle or in DD showed higher growth rates than in animals injected diurnally. No differences were found when animals were injected at the same time with cultures synchronized 12 hours apart. Similar experiments performed with B16 melanoma cells showed higher tumor growth rates in animals injected at the beginning of the night compared to those injected in the daytime. A higher tumor growth rate than that in controls was observed when mice were injected with knocked-down clock gene Bmal1 cells. Finally, when we compared day/ night administration of different doses of the proteasome inhibitor Bortezomib (0.5-1.5 mg/kg) in tumor-bearing animals, we found that low-dose chemotherapy displayed higher efficacy when administered at night. Results suggest the existence of a precise temporal control of tumor growth and of drug efficacy in which the host state and susceptibility are critical. K E Y W O R D SBortezomib, cancer chronotherapy, circadian clock, light/dark differences, tumor growth 2 of 16 | WAGNER Et Al.

Adjusting the Clock: the Importance of Circadian Rhythms in the Development of Glioblastomas and Its Intervention as a Therapeutic Strategy

“…Similar results recently showed a reduction in PER1 expression in high-grade gliomas [222]. In agreement with these observations, tumors generated by injection of cells isolated from a malignant peripheral nerve sheath tumor exhibited lower Per1 mRNA levels than normal tissue [21]. One possible explanation linking the low levels of Per1 mRNA and protein with a higher tumor malignancy may be likely associated with the opposite relationship found between its expression and the phospholipid biosynthesis required for the genesis of the new membranes and other essential processes during cell growth and proliferation, as was observed in a non-malignant fibroblast cell line [161].…”

“…Recent results from our laboratory showed significant differences in Bortezomib efficacy on tumor-bearing mice when the drug was administered at the beginning of the day in the light phase or at night in the dark. We showed that a chemotherapeutic scheme in which a high dose (1.5 mg/kg) of Bortezomib was administered wholly inhibited tumor growth at both times; whereas a low dose of Bortezomib (0.5 mg/kg) displayed higher efficacy to impair tumor growth when delivered at night compared to diurnal treatment [21] (Figure 2). A recent retrospective study on GBM patients reported that the administration of TMZ in the morning was correlated with an increased OS in MGMT-methylated patients compared with those subjected to evening treatment.…”

“…In this study, a cell line isolated from a malignant peripheral nerve sheath tumor generated in NPcis mice (an animal model for the human neurofibromatosis type I) was used as a glioma model after being injected into C57BL/6 animals and tumor growth evaluated. The results showed that, after the knockdown of Bmal1 using CRISPR/Cas9, tumors grew faster than those from control cells [21]. Suliman Khan and colleagues (2019) identified oncogenes and tumor suppressor genes that show significant variations in their expression in brain tissues from animals exposed to a CJL protocol.…”

“…Chronotherapy has emerged as a new concept that proposes the differential administration of drugs throughout the 24-hours daytime to improve drug efficiency and reduce cancer toxicity and side effects of the treatment. This strategy has been applied only recently to treat CNS tumors because it was shown a differential response to the proteasome inhibitor Bortezomib in a murine model [21] and that TMZ administration in human and murine GBM cells in culture is dependent on clock gene expression [22]. In this review, we analyze and discuss the current literature regarding GBM biology, the role of the circadian clock in tumor progression, specifically on GBM, and the potential of chronotherapy as an original approach to improve the treatment for this type of tumor.…”

Adjusting the Molecular Clock: The Importance of Circadian Rhythms in the Development of Glioblastomas and Its Intervention as a Therapeutic Strategy

“…Chronotherapy has emerged as a new concept that proposes the differential administration of drugs throughout the 24-h daytime to improve drug efficiency and reduce cancer toxicity and side effects of the treatment. This strategy has been applied only recently to treat CNS tumors because a differential response to the proteasome inhibitor Bortezomib was shown in a murine model [ 21 ] and that TMZ administration in human and murine GBM cells in culture is dependent on clock gene expression [ 22 ]. In this review, we analyze and discuss the current literature regarding GBM biology, the role of the circadian clock in tumor progression, specifically on GBM, and the potential of chronotherapy as an original approach to improve the treatment for this type of tumor.…”