Table 1 Pharmacological inhibition of HIF-1α and HIF-2α in GBM.
From: Preclinical and clinical advances to overcome hypoxia in glioblastoma multiforme
Transcription factor | Level of inhibition | Molecule | Mode of action | Studies results |
|---|---|---|---|---|
HIF-1α | mRNA | OKN-007 | Downregulates HIF-1 mRNA | - Opened the BBB for few hours in a mouse model [89] - Reduced the expression of HIF-1, GLUT-1, and VEGFR2 in mice models under hypoxic conditions [7] - Sensitized TMZ-resistant GBM, decreased tumor volume, and normalized tumor blood vasculature in a rat model [90] |
Protein | 103D5R | Inhibits HIF-1 translation | - Downregulated VEGF and Glut-1 in GBM, breast, and prostate cell lines [91] | |
KC7F2 | Inhibits HIF-1 translation | - Decreased the effective dose of TMZ and effectively reduced the aerobic glycolysis of U-87 MG cell line in vitro [92] | ||
Cardiac glycosides (Proscillardin A, Gamabufotalin, Anvirzel™) | Inhibit the HIF-1 protein but do not downregulate its expression | - Proscillardin A reduced migration in GBM via the activation of GSK-3β and the phosphorylation of EB1 and the alteration of microtubule dynamics (U-87 MG, U-251 MG, and GBM stem-like cells GBM6, GBM9) [93] - Gamabufotalin increased GBM sensitivity to TMZ and contributed to the overphosphorylation of p38 through ATP1A3 and AQP4 (U87, U251, LN229, LN18, A172 and T98 cells) [94] - Anvirzel™ reduced GBM growth in vitro and decreased the expression of GSK-3β and HIF-1α (U-87 MG) [95] | ||
PX-478 | Inhibits HIF-1 deubiquitination | - Downregulated VEGF expression - Decreased PD-L1 expression under hypoxia (U-251 MG, U343, GL-261) [96] | ||
Vorinostat | Inhibits HIF-1α nuclear translocation via acetylation of associated chaperon Hsp90 | - Specific inhibition of HDAC6, decreased EB1 expression, and suppressed microtubule instability in GBM cell line (U87-MG, GL261, and GBM6) [97] - A combination with Trichostatin-A inhibited Wnt-dependent pathways, and reduced cell proliferation of primary GBM culture [98] | ||
Panobinostat | Induces prolonged hyperacetylation of the histone protein (histone deacetylase inhibitor) | - Induced metabolic reprogramming by lowering ATP levels, suppressing c-Myc protein levels, and elevating PGC1α and PPARD, involved in oxidative metabolism in vitro (LN229 and U-87 MG) [99] - Upregulated the estrogen receptor ERβ 1 isoform, a tumor suppressor in GBM in vitro (U87 and U251) [100] | ||
Topotecane | Inhibits the transcriptional activity and accumulation of HIF | - Inhibited SUMOylation, decreased levels of CDK6 and HIF-1α, and altered the cell cycle in vitro (U251, LN229, and Mz18) [101] | ||
Icaritin | Suppresses de novo synthesis and promotes degradation of HIF-1 | - Decreased the expression of HSP-70, HSP-60, and HIF-1α in an in vitro model of cerebral ischemia (PC12 cell line) [102] - Suppressed the IL-6/Stat pathway, reduced glycolysis and decreased cell viability of human GBM cell lines in vitro (U87 and T98G) [103] - Inhibited the migratory potential of U-87 MG in vitro via PTEN/Akt signaling pathway [104] | ||
Binding to HRE | Acriflavine | Blocks the binding of HIF-1 to DNA | - Inhibited tumor growth in vivo in orthotopic glioma models (rodents) via intratumoral administration with biodegradable polymeric wafers (U87, GL2361, F98, 9 L gliosarcoma, GB1A (0913), and JHH1113) [105] - Suppressed tumor growth in vivo when combined to photodynamic therapy (U251 and GL261) [106] | |
Echinomycin | Blocks the binding of HIF-1 to DNA | - Induced apoptosis, inhibited tumor growth in vivo, and reduced the activation of AKT pathway through PDGF-D and PDGFRα axis inhibition (U251, U87MG, GL261, and primary GBM) [107] | ||
KCN1 | Inhibits HIF-1 transcriptional activity | - Interfered in the interaction between HIF-1 and its coactivators p300/CBP (U251MG, D54MG, D645MG, and LN443) and penetrated the BBB in a mouse GBM model (LN229) [108] | ||
HIF-2α | Protein binding | PT2385 | Blocks allosterically the dimerization of HIF-2α with HIF-β | - PT2385 alone reduced the OS of an in vivo mouse model (patient-derived GBM), however, no increase was detected in OS after combining PT2385 to conventional treatments (RT and TMZ) [8] |
