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.
Keywords: alkylating drugs; inhibitor of apoptosis (IAP); malignant glioma; senescence.