Senotherapeutics in malignant brain cancer therapy

Abstract

Purpose of Review: Malignant brain cancer, the most severe form is glioblastoma (GBM), has a dismal prognosis, despite maximal resection followed by radio-chemotherapy. First line therapeutics are alkylating drugs, notably the DNA-methylating temozolomide (TMZ), administered concomitantly with radiation. Radio-chemotherapy induces not only apoptosis, but also cellular senescence in GBM cells. Senescent cells change the tumor microenvironment, cause an inflammatory response in the affected area and can be reactivated, contributing to recurrences. To eliminate therapy-induced senescent cells, senotherapeutics have gained attention. Here, we describe the pathways triggered in GBM cells leading to cellular senescence and update drugs and natural compounds acting as senolytics, senomorphics and senopreventics.

Recent Findings: There is an increasing amount of data showing that temozolomide induces cellular senescence, which is even the main response of GBM cells following treatment. We outline the mechanism of senescence in glioblastoma cells and show that it rests on some unique cellular responses that may explain the low curability and aggressiveness of glioblastoma. Thus, senescent GBM cells are incompletely blocked in G2 following temozolomide treatment and undergo endoreduplications. This is presumably fostered by inactivation of CDKN2A, which is frequently mutated in gliomas.

Summary: Since cellular senescence is a key event induced by temozolomide and radiation in GBM cells, it is reasonable to conclude that glioma cells cannot be completely eliminated, neither by radiation or chemotherapy alone nor in combination. Based on the data, new treatment options with senopreventics, senolytics and senostatics/senomorphics as important supportive medication during or after radiochemotherapie are discussed.