Abstract
Simple SummaryDespite extensive research, malignant glioma remains the most aggressive and fatal type of brain tumor. Following resection, therapy is based on radiation concomitant with the methylating agent temozolomide (TMZ), followed by adjuvant high-dose TMZ. In previous work, we showed that following TMZ exposure, most glioma cells evade apoptosis and enter a senescent state and are thereby protected against anticancer therapy. Senescent cells may escape from senescence, contributing to the formation of recurrences or can induce the senescence-associated secretory phenotype (SASP), which may impact therapy success. Therefore, direct targeting of senescent cells might be favorable to improve the effect of TMZ-based anticancer therapy. Here we show that during TMZ-induced senescence in glioblastoma cells, the antiapoptotic factors c-IAP2 and Bcl-2 are responsible for the prevention of cell death and that inhibition of these factors by BV6 and venetoclax effectively kills senescent glioblastoma cells.Therapy of malignant glioma depends on the induction of O6-methylguanine by the methylating agent temozolomide (TMZ). However, following TMZ exposure, most glioma cells evade apoptosis and become senescent and are thereby protected against further anticancer therapy. This protection is thought to be dependent on the senescent cell anti-apoptotic pathway (SCAP). Here we analyzed the factors involved in the SCAP upon exposure to TMZ in glioblastoma cell lines (LN-229, A172, U87MG) and examined whether inhibition of these factors could enhance TMZ-based toxicity by targeting senescent cells. We observed that following TMZ treatment, c-IAP2 and Bcl-2 were upregulated. Inhibition of these SCAP factors using non-toxic concentrations of the small molecule inhibitors, BV6 and venetoclax, significantly increased cell death, as measured 144 h after TMZ exposure. Most importantly, BV6 and venetoclax treatment of senescent cells strongly increased cell death after an additional 120 h. Moreover, Combenefit analyses revealed a significant synergy combining BV6 and venetoclax. In contrast to BV6 and venetoclax, AT406, embelin, and TMZ itself, teniposide and the PARP inhibitor pamiparib did not increase cell death in senescent cells. Based on these data, we suggest that BV6 and venetoclax act as senolytic agents in glioblastoma cells upon TMZ exposure.
Highlights
Among the different subtypes of brain cancer, glioblastomas (WHO grade IV) account for ~60% of high-grade gliomas [1]
As a tumor-suppressing mechanism, the senescence-associated secretory phenotype (SASP), which is characterized by secretion of multiple immune factors, including interleukins, chemokines, growth factors, and matrix metalloproteinases [15,16,17], can reinforce the growth arrest by increasing ROS production and by enhancing the DNA damage response [17,18]
Cell death was executed by apoptosis and necrosis, as shown by annexinV/PI-staining (Figure 1B)
Summary
Among the different subtypes of brain cancer, glioblastomas (WHO grade IV) account for ~60% of high-grade gliomas [1]. In addition to apoptosis, TMZ strongly induces senescence in glioma cells [7,8]. As a tumor-suppressing mechanism, the senescence-associated secretory phenotype (SASP), which is characterized by secretion of multiple immune factors, including interleukins, chemokines, growth factors, and matrix metalloproteinases [15,16,17], can reinforce the growth arrest by increasing ROS production and by enhancing the DNA damage response [17,18]. SASP induces an inflammatory response and activates immune cells, which eliminate senescent tumor cells [19,20]. SASP factors act as potent tumor promoters, enhancing malignant tumorigenesis. The SASP can enhance the proliferation of neoplastic epithelial cells [21] and promote EMT [22,23] as well as tumor growth in vivo [24,25]
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