Table 2.
Licensed drugs targeting Wnt or PAM pathways that have shown potential as repurposed anticancer agents in GBM therapy determined by in vitro and in vivo research and clinical trials [241].
| Drug | Suggested Mechanism of Action | IC50 | Outcome | References |
|---|---|---|---|---|
| Chloroquine | Autophagy induction, inhibition of MMP-2 activity, TGF-β secretion and signaling | 30 μΜ (U251, LN229, U87MG) 40 μΜ (U251-TMZR, LN229-TMZR, U87MG-TMZR) |
Primary cultures of GBM cell lines and specimens showed a 50% reduction in proliferation. | [242,243] |
| Hydroxy-chloroquine | Autophagy induction | - | Hydroxy-chloroquine eliminated TMZ-resistant glioma cells. | [242] |
| Mefloquine | Autophagy induction | 10 μΜ (U251, LN229, U87) 15 μΜ (U251-TMZR, LN229-TMZR, U87-TMZR) |
Mefloquine was capable to killing U251 and U251-TMZ resistant cells at far lower doses than chloroquine. | [242,244] |
| Quinacrine | Autophagy induction | 5 μΜ (U251, LN229, U87) 8 μΜ (U251-TMZR, LN229-TMZR, U87-TMZR) |
50 mg/kg of quinacrine substantially slowed the growth of tumors in a subcutaneous human xenograft U87MG model. | [242,245] |
| Pyrvinium pamoate | Inhibition of Wnt/β-catenin signaling | 239.8 nmol/L (BT241), 122.5 nmol/L (BT486) | For 48 h, 200 nmol/L of pyrvinium decreased CD133POS cell fractions in primary (BT428) and recurrent (BT 566) GBM cells. | [246] |
| Itraconazole | Inhibition of cell proliferation | - | Itraconazole inhibited the proliferation of GBM cells in vitro (2–80 μM, U87MG and rat C6 glioma cells) and in vivo (75 mg/kg, nude mice with U87MG subcutaneous xenografts). | [247] |
| Salinomycin | OxPhos inhibition in mitochondria | - | Salinomycin decreased the cell viability of GL261 neurospheres and GL261 adherent cells. Salinomycin depleted neurosphere-forming GL261 stem cells from tumorspheres. | [248] |
| Minocycline | Growth inhibition, autophagy induction, caspase-3 mediated apoptosis | 30 μM (C6) | 50 μM of minocycline decreased the cell viability of U87MG, U251 and C6 glioma cells; 20 or 100 mg/kg of minocycline (IP) showed slower tumor growth compared controls in Mice injected with C6 cells. | [249] |
| Chlorpromazine | Inhibition of PAM signaling, autophagy induced cell death | 18.8–27.7 μM (C6) 15 μM (SH-SY5Y) |
Cell viability was significantly lowered in cells treated with chlorpromazine (≥20 μM) for 24 h. Overall survival greatly improved for U251-TMZR orthotopic mouse xenograft models. | [250] |
| Quetiapine | Inhibition of Wnt/β-catenin signaling | - | Relatively high doses of quetiapine (>25 μM) may inhibit cell proliferation by retarding cell cycle in the G2-M phase; 20 mg/kg of quetiapine (IP) alone or combined with TMZ slowed tumor development in orthotopic xenograft mouse model. | [251] |
| Lithium | Inhibition of GSK-3 activation | - | 20 mM lithium for 48 h reduced in viability of 20% of U87MG cells. Through GSK-3 inhibition, lithium concentrations above 5 mM can affect the proliferation, apoptosis and migration of glioma cells. Combination of 1.2 mM lithium and TMZ increased cell death in TP53wt glioma cells and prevented tumor growth in vivo with increased median survival times of mice. | [252,253] |
| Fluvoxamine | Inhibition of FAK and Akt/mTOR | 30 μM | 20–30 μM of fluvoxamine inhibited lamellipodia formation, migration and invasion of U87MG and U251 cells in vitro; 50 mg/kg of fluvoxamine inhibited GBM cell invasion and prolonged survival in mice bearing glioma tumors. | [254] |
| Imipramine | Autophagy induction; inhibition of PI3K/Akt/mTOR | - | 60 μM of imipramine was cytotoxic and strongly reduced colony formation of U87MG and C6 cells, but not primary cultured rat astrocytes; 10 μM of imipramine inhibited mitochondrial activity relative to oxygen content in the atmosphere (from 6% in hypoxia, 11% in mild hypoxia, to 19% in medium re-oxygenated at 26% oxygen). | [255,256,257] |
| Dimethyl fumarate | Autophagy induction | - | - | [258] |
| Simvastatin | Inhibition of cell growth and migration; inhibition of Ras/ERK and Ras/Akt pathways to induce caspase-3 mediated apoptosis; downregulation of PI3K/Akt | - | 10 μM of simvastatin was cytotoxic to U251 and U87MG by inducing aopotosis. | [259,260,261] |
| Mevastatin, fluvastatin | Inhibition of cell growth; inhibition of Ras/ERK and Ras/Akt; induction of apoptosis | 0.922 μM (A 172) | 5 and 10 μM of mevastatin and fluvastatin are cytotoxic. | [259,261] |
| Mibefradil | Inhibition of tumor growth; cell cycle inhibition; activation of pro-apoptotic survivin and BAX pathways; inhibition of Akt/mTOR | - | 2.5–5 μmol/L greatly inhibited cell growth and enhanced the inhibition of GSC growth by TMZ; 24 mg/kg (bodyweight) of mibefradil (oral gavage) significantly inhibited growth of tumor. | [262,263] |
| Losartan | Reducing tumor and cell growth; reduced number of capillary blood vessels; decreased levels of VEGF, PDGF and FGF; apoptosis induction | [193,264] | ||
| Metformin | Autophagy and induction of apoptosis; activated AMPK and down-regulation of Akt/mTOR pathway; inhibition of CLIC1 activity with G1 cell arrest | - | 10 mM significantly decreased GBM cell proliferation (U87MG, U251, LN18 and SF767). | [265,266] |
| Pioglitazone | Inhibition of β-catenin expression; reduced cell viability; apoptosis induction | 85 μM (U87MG) | 100–200 μM significantly reduced the viability of glioma cells (U251, T98G, and U87MG) in a concentration- and time-dependent manner; 100 μM pioglitazone via reducing MMP-2 expression can inhibit U251 cell migration; 50 μM significantly reduced the metabolic activity of G144 cells; 10 μM promoted a minor decrease in metabolic activity in GliNS2 cells. | [267,268] |
| Aprepitant | Enhanced blockage in Akt phosphorylation due to NK-1 signaling | 32 µM (GAMG) | Maximum inhibition at 70 μM after 48 h, with no surviving cells (GAMG glioma cell line). | [269] |
| Cimetidine | GSK-3β inhibition; reduction in endogenous receptors required for cell adhesion and migration | - | Decreased growth rates of U373 GBM and 9L gliosarcoma cells at concentrations equal to or higher than 100 mM; 100 and 1000 mM cimetidine significantly decreased migration of both cell lines; doses <100 mM did not affect cell cycle kinetics or apoptosis. | [270,271] |
| Ivermectin | Deactivation of the Akt/mTOR pathways | - | 1, 5, and 10 μM inhibited proliferation of U87MG and T98G cells in a dose-dependent manner with ED50 of ∼5 μM. | [272] |
| Rapamycin | Interfering with the AMPK/mTORC1 axis | [108] | ||
| Gefitinib and Erlotinib | ATP-competitive and reversible EGFR inhibitors | [141] | ||
| Sonolisib | Reduced invasion and angiogenesis in GBM cell lines in vitro; improved survival in orthotopic xenograft models | [136,137] | ||
| Buparlisib | Well-tolerated, BBB permeable PI3K inhibitor (most often utilized PI3K inhibitor in clinical studies for GBM therapy) | [135] | ||
| Pimozide | Inhibition of migration and survival of GBM cells in a STAT5- dependent manner | [130] |