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

Beltzig, Lea, Christmann, Markus, Kaina, Bernd·2022·Cells
DOI 10.3390/cells11162588PMC PMC9406955
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Abstract

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.

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  • Chloroquine has demonstrated senolytic activity in therapy-induced senescent glioblastoma cells by blocking autophagosome-lysosome fusion and reducing senescence markers.

    “chloroquine has demonstrated senolytic activity in therapy-induced senescent glioblastoma cells by blocking autophagosome-lysosome fusion and reducing senescence markers50”

    From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [50]

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Metadata

Authors
Beltzig, L., Christmann, M., & Kaina, B.
Venue
Cells
Publisher
MDPI AG
Published
2022-08-19
Volume
11
Issue
16
Pages
2588
ISSN
2073-4409
DOI
10.3390/cells11162588
PMC
PMC9406955
Cited by
50
References
10
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
Deutsche Forschungsgemeinschaft (DFG KA724/31-1, CH 655/6-1)

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