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 lines102–104. + 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$\mathrm{\alpha }$- 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.