Table 1 Selection of candidate senolytic/senomorphic therapies in glioma.
Drug family | Senotherapeutic (FDA status) | Mechanism | In vitro and in vivo evidence |
|---|---|---|---|
Anti-apoptotic Bcl-2 family protein inhibitors | ABT-263/ navitoclax (in clinical trials) | Bcl-2, Bcl-xL, and Bcl-W inhibitor | + Apoptosis induced at lower IC50 in senescent, than non-senescent, glioma cells across multiple cell lines102,103,104. + Increased animal survival in pre-irradiated in vivo CT-2A;13 also in radiation-naïve U87MG IDH1-R132H and PDX GBM164 models103. -Drug toxicities, including thrombocytopenia106. |
Venetoclax (FDA approved) | Bcl-2 inhibitor | + Venetoclax after initial round of TMZ increases cell death in in vitro LN229108. - No differential impact of drug on senescent human glioma cells as compared to non-senescent cells104. | |
Flavonoids | Quercetin, in combination with dasatinib (in clinical trials53) | SCAP targeting, including tyrosine kinases (dasatinib), PI3K/AKT/mTOR, p53/MDM2/p21 and HIF1\({\rm{\alpha }}\)- related pathways (quercetin) | + In other disease models, decrease in circulating SASP factors, and clearance of senescent cells in adipose tissue15,53,109. - No substantial impact on senescent in vitro GBM39 human glioma cells104. |
Fisetin (in clinical trials) | Inhibition of multiple pathways, including PI3K/AKT/mTOR and AMPK | + Decrease in senescent cells after TMZ-induced senescence in LN229 and A172 cells102. - No senolytic impact on senescent in vitro GBM6, 39, or 76 cells104. | |
Inhibitors of apoptosis (IAP) family inhibitor | BV6 (not available clinically) | Inhibition of c-IAP1 and c-IAP2 | + Selectively ablate in vitro LN229 and A172 after TMZ93. + Combination with venetoclax and TMZ increase cell death as compared to BV6, venetoclax, +/- TMZ99. |
Antimalarial | Artesunate | Poorly defined | + Senolytic activation in TMZ-treated LN229, A172, and U87MG in vitro cells86, as well as GBM stem-like cells99. |
Hsp90 inhibitors | Onalespib (in clinical trials99) | Inhibitor of Hsp90 | + In combination with TMZ, increased survival in intracranial U251 and GS811 mouse intracranial xenografts as compared to TMZ alone117. +/- Cytotoxic impact in GBM6, 39, and 76, albeit not specific to senescent cells104. |
Senomorphics, i.e SASP inhibition | Tocilizumab (FDA approved) | IL-6 therapeutic monoclonal antibody | + Decreased growth of TMZ-treated subcutaneous flank U251 glioma121. + Targeting IL6R-alpha or IL-6 with shRNA decrease glioma stem cell growth71. + IL-6/IL-6R knockdown increase survival in intracranial T3359 GSC models71. |
