Table 6 FOXO3 and treatment opportunities in glioma
Treatment | Cancer type and cell line | Drug type | Target genes | Role of FOXO3 | Effect on FOXO3 | Model | Description |
|---|---|---|---|---|---|---|---|
Stem-Like Glioma-Initiating Cells | Biguanide for diabetes type 2 | AMPK/FOXO3 | TS | By increasing AMPK, activates FOXO3 | In vivo/In vitro | • Differentiation of stem-like glioma-initiating cells • ↓Tumor-Initiating Potential | |
BMP4 + TMZ [183] | GBM GSC | Chemotherapy agent and natural protein | EGFR/AKT/FOXO3a/BIM | TS | Inhibition of Akt causes FOXO3 translocation in high EGFR cells | In vitro | • ↑Differentiation and • apoptosis in high expressing EGFR cells |
GSK2126458 + LY2874455 [187] | GSC | PI3K/mTOR and FGFR inhibitors | 14–3-3τ/CLK2/AKT/FOXO3a/p27 | TS | CLK2 regulates AKT phosphorylation through PP2A activity | In vivo/In vitro | • ↑ Sub-G1 phase, suggesting apoptosis induction • Depletion of CLK2 enhanced the effect of FGFR inhibitors in GSCs |
LY294002 [179] | GBM | PI3K pharmacological inhibitor | AKT/FOXO3a/p27 | TS | FOXO3a nuclear translocation | In vitro | • G1 arrest through retention of activated FOXO3a |
NVP-BEZ235 [137] | GBM | PI3K pharmacological inhibitor | AKT/FOXO3/ OCT4 and SOX2 | TS | FOXO3a nuclear translocation and binding to OCT4 promoter | In vitro | • Induced OCT4 in glioblastoma cells with intact FOXO3 activity, not mutant cells |
Erlotinib and trifluoperazine [185] | GBM | EGFR inhibitor and FOXO3 activator | EGFR/Akt/FOXO3a/p27 | TS | Inhibits EGFR and FoxO3a phosphorylation | In vitro | • Erlotinib induces FOXO3a dephosphorylation and nuclear accumulation • ↓Growth • Their combination synergistically reduces growth |
1NVP-BEZ235 and/or 2SL327/U0126 [196] | GBM stem like cells | 1.dual PI3K/mTOR inhibitor 2.MEK inhibitor | Akt/FOXO3a/p27 and ERK/FOXO3a/p27 | TS | Prevents FOXO3a phosphorylation | In vitro | • Combination therapy caused nuclear accumulation of FOXO3a and βIII-tubulin expression as stem cell markers, inhibiting self-renewal and tumorigenicity |
Hydrogen peroxide [186] | GICs | ROS | p38MAPK/FOXO3 | TS | MAPK activates FOXO3 | In vitro | • ↓Self-renewal and induces differentiation |
TIC10 [197] | GBM | TRAIL inducer | TC10/TRAIL/ERK-Akt/FOXO3a/TRAIL | TS | TIC10 inactivates Akt and ERK by cooperatively inducing TRAIL | In vivo/In vitro | • ↑Survival apoptosis • Cytotoxicity against TMZ resistant cells |
B10 [209] | GBM | Natural product /Botulinic acid derivative | B10/SIRT1/FOXO3a/Bim/PUMA/Bax | TS | B10 downregulates SIRT1 expression and activates FOXO3a | In vivo/In vitro | • ↑Cytotoxicity and mitochondrial dysfunction |
Pt-1-DMCa [215] | GBM | platinum-maurocalcin conjugate | Src/PI3K/AKT/FOXO3a /Bim and PTEN | TS | Pt-1-DMCa induces accumulation of non-phosphorylated FOXO3a in the nucleus | In vitro | • ROS-dependent FoxO3a-mediated apoptosis • ↑PTEN |
Fenofibrate [217] | GBM | lipid-lowering drug | FOXO3A/Bim | TS | FoxO3A subcellular localization | In vitro | • ↑Mitochondrial-dependent apoptosis |
Icariside II [220] | GBM | Natural product and bioactive flavonoid | Akt/FOXO3a/p21 and p27 | TS | ICA II inhibits the phosphorylation and activation of Akt and leads to FOXO3a nuclear translocation | In vitro | • ↓Proliferation • ↑Cell cycle arrest and apoptosis |
Z-ajoene [234] | GBM stem cells | Natural product and garlic-derived compound | Akt/ FOXO3a | NA | decreased FOXO3A through dephosphorylation of AKT signaling | In vitro | • ↓ Sphere growth |
Dichloroacetate (DCA) [235] | rat GSCs | An analogue of acetic acid | Foxo3 | TS | DCA may increase the transcriptional activity of Foxo3 | In vivo/In vitro | • ↓Proliferation • ↑ Aapoptosis |