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Targeting c-IAP1, c-IAP2, and Bcl-2 Eliminates Senescent Glioblastoma Cells Following Temozolomide Treatment
Christian Schwarzenbach1, Larissa Tatsch1, Juliana Brandstetter Vilar1
1Department of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
Abstract:
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.
Insights
Temozolomide (TMZ) therapy for glioma induces senescence, protecting cells. Inhibiting senescent cell anti-apoptotic pathways with BV6 and venetoclax enhances TMZ
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Malignant glioma therapy relies on temozolomide (TMZ) to induce O6-methylguanine.
- Glioma cells often evade apoptosis post-TMZ, becoming senescent and resistant to treatment.
- This resistance is linked to the senescent cell anti-apoptotic pathway (SCAP).
Purpose of the Study:
- To analyze SCAP factors in glioblastoma cells after TMZ exposure.
- To investigate if inhibiting SCAP factors can enhance TMZ toxicity by targeting senescent cells.
Main Methods:
- Glioblastoma cell lines (LN-229, A172, U87MG) were treated with TMZ.
- Expression of SCAP factors (c-IAP2, Bcl-2) was analyzed.
- Small molecule inhibitors (BV6, venetoclax) were used to inhibit SCAP factors.
- Cell death was measured after TMZ and inhibitor treatments.
- Synergistic effects were analyzed using Combenefit.
Main Results:
- TMZ treatment upregulated c-IAP2 and Bcl-2 in glioma cells.
- Inhibiting c-IAP2 and Bcl-2 with BV6 and venetoclax significantly increased TMZ-induced cell death.
- BV6 and venetoclax treatment of senescent cells markedly increased cell death.
- A significant synergy was observed when combining BV6 and venetoclax.
- Other agents (AT406, embelin, teniposide, pamiparib) did not enhance senescent cell death.
Conclusions:
- BV6 and venetoclax demonstrate senolytic activity in TMZ-exposed glioblastoma cells.
- Targeting SCAP factors offers a potential strategy to overcome TMZ resistance in glioma.
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