Abrogation of Cellular Senescence Induced by Temozolomide in Glioblastoma Cells: Search for Senolytics

A first-line therapeutic for high-grade glioma, notably glioblastoma (GBM), is the DNA methylating drug temozolomide (TMZ). Previously, we showed that TMZ induces not only apoptosis and autophagy, but also cellular senescence (CSEN). We presented the hypothesis that GBM cells may escape from CSEN, giving rise to recurrent tumors. Furthermore, the inflammatory phenotype associated with CSEN may attenuate chemotherapy and drive tumor progression. Therefore, treatments that specifically target senescent cells, i.e., senolytic drugs, may lead to a better outcome of GBM therapy by preventing recurrences and tumor inflammation. Here, we tested Bcl-2 targeting drugs including ABT-737, ABT-263 (navitoclax), several natural substances such as artesunate, fisetin and curcumin as well as lomustine (CCNU) and ionizing radiation (IR) for their senolytic capacity in GBM cells. Additionally, several proteins involved in the DNA damage response (DDR), ATM, ATR, Chk1/2, p53, p21, NF-kB, Rad51, PARP, IAPs and autophagy, a pathway involved in CSEN induction, were tested for their impact in maintaining CSEN. Treatment of GBM cells with a low dose of TMZ for 8-10 days resulted in >80% CSEN, confirming CSEN to be the major trait induced by TMZ. To identify senolytics, we treated the senescent population with the compounds of interest and found that ABT-737, navitoclax, chloroquine, ATMi, ATRi, BV-6, PX-866 and the natural compounds fisetin and artesunate exhibit senolytic activity, inducing death in senescent cells more efficiently than in proliferating cells. Curcumin showed the opposite effect. No specific effect on CSEN cells was observed by inhibition of Chk1/Chk2, p21, NF-kB, Rad51 and PARP. We conclude that these factors neither play a critical role in maintaining TMZ-induced CSEN nor can their inhibitors be considered as senolytics. Since IR and CCNU did not exhibit senolytic activity, radio- and chemotherapy with alkylating drugs is not designed to eliminate TMZ-induced senescent cancer cells.

 

Comments:

The passage you provided discusses the use of temozolomide (TMZ) as a first-line therapeutic for high-grade gliomas, particularly glioblastoma (GBM), and its induction of cellular senescence (CSEN) in GBM cells. It suggests that GBM cells may escape from CSEN, leading to recurrent tumors, and that the inflammatory phenotype associated with CSEN may hinder chemotherapy and drive tumor progression. The passage proposes that targeting senescent cells with senolytic drugs could improve GBM therapy outcomes by preventing recurrences and tumor inflammation.

To investigate potential senolytic drugs in GBM cells, the researchers tested Bcl-2 targeting drugs such as ABT-737 and ABT-263 (navitoclax), as well as natural substances like artesunate, fisetin, and curcumin. They also examined lomustine (CCNU) and ionizing radiation (IR). Additionally, they evaluated various proteins involved in the DNA damage response (DDR), including ATM, ATR, Chk1/2, p53, p21, NF-kB, Rad51, PARP, IAPs, and autophagy, which is associated with CSEN induction.

The results showed that treatment with a low dose of TMZ induced more than 80% CSEN in GBM cells, confirming CSEN as the primary effect of TMZ. Among the compounds tested, ABT-737, navitoclax, chloroquine, ATMi, ATRi, BV-6, PX-866, fisetin, and artesunate exhibited senolytic activity, causing death in senescent cells more effectively than in proliferating cells. However, curcumin had the opposite effect, indicating it did not possess senolytic properties. Inhibition of Chk1/Chk2, p21, NF-kB, Rad51, and PARP did not have a specific effect on CSEN cells, suggesting that these factors do not play a critical role in maintaining TMZ-induced CSEN, nor can their inhibitors be considered senolytics. The researchers also found that IR and CCNU did not exhibit senolytic activity, indicating that radiotherapy and chemotherapy with alkylating drugs are not designed to eliminate TMZ-induced senescent cancer cells.

In summary, the study highlights the potential of senolytic drugs, such as ABT-737, navitoclax, chloroquine, ATMi, ATRi, BV-6, PX-866, fisetin, and artesunate, to selectively target and eliminate senescent GBM cells induced by TMZ. These findings suggest that targeting senescent cells may offer a promising strategy to enhance GBM therapy outcomes by preventing tumor recurrence and reducing inflammation. However, further research is needed to validate these results and develop effective senolytic therapies for GBM.