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

Abstract

Gliomas are solid tumors of the central nervous system (CNS) that originated from different glial cells. The World Health Organization (WHO) classifies these tumors into four groups (I–IV) with increasing malignancy. Glioblastoma (GBM) is the most common and aggressive type of brain tumor classified as grade IV. GBMs are resistant to conventional therapies with poor prognosis after diagnosis even when the Stupp protocol that combines surgery and radiochemotherapy is applied. Nowadays, few novel therapeutic strategies have been used to improve GBM treatment, looking for higher efficiency and lower side effects, but with relatively modest results. The circadian timing system temporally organizes the physiology and behavior of most organisms and daily regulates several cellular processes in organs, tissues, and even in individual cells, including tumor cells. The potentiality of the function of the circadian clock on cancer cells modulation as a new target for novel treatments with a chronobiological basis offers a different challenge that needs to be considered in further detail. The present review will discuss state of the art regarding GBM biology, the role of the circadian clock in tumor progression, and new chrono-chemotherapeutic strategies applied for GBM treatment.

Chronotherapy in Glioblastoma: state of the art and future perspectives

“…Based on the results described above together with the recently reported data, 89 future targeting of BMAL1 , CLOCK or genes from the PER family may represent promising therapeutic targets for treatment of glioblastoma.…”

Pharmacological modulation of the cytosolic oscillator affects glioblastoma cell biology

“…GBM is a highly vascularized and invasive brain tumor with a poor prognosis. Median patient survival after diagnosis is 12-15 months and there are no full curative therapies (reviewed in [42]). Recent evidence in the field shows that circadian clock function should be considered a novel target to design new therapeutic strategies or improve the current approaches to treat high-grade gliomas.…”

“…Based on the World Health Organization (WHO) classification, GBMs are grade 4 brain tumors resistant to conventional therapies; they represent 45.2% of all malignant central nervous system (CNS) tumors and 80% of all primary malignant CNS tumors [23]. The standard of care treatment is the Stupp protocol, which combines radiotherapy followed by the administration of the DNA-alkylating chemotherapeutic temozolomide (TMZ) (reviewed in [24]). Though the TMZ regimen was approved by the US Food and Drug Administration (FDA), its chemotherapeutic efficiency is poor and most patients relapse [25].…”

Circadian Gene cry Controls Tumorigenesis through Modulation of Myc Accumulation in Glioblastoma Cells

“…In the recent years, the study of alterations in circadian rhythm genes has emerged in different types of cancer, including GB [20]. Previous reports suggested that circadian rhythm genes play essential roles in different aspects of tumor progression.…”