Fig. 1: Schemes of cell signalling regulation by 2-OHOA treatment and clinical trial.

a Mechanism of action of 2-OHOA. (1) 2-OHOA regulates the cell membrane composition by both direct incorporation into the lipid bilayer and regulation of important lipid metabolism enzymes, such as SMS-1, stearyl CoA desaturase 1 (SCD1), phospholipases 1 and 2 (PLA1/2), which regulate the levels and types of sphingolipids (SLs) and phospholipids (PLs). (2) Among other structural effects on the lipid bilayer, these changes in lipid composition regulate the raft-to-nonraft lipid balance, which causes translocation of numerous proteins from or to the membrane (e.g., PKC and Ras). (3) The presence or absence of peripheral membrane signalling proteins triggers or hampers, respectively, important signalling cascades. (4) These signalling cascades control glioma cell’s physiology, inducing unfolded protein response (UPR), endoplasmic reticulum (ER) stress, cell cycle arrest, cell differentiation, oxidative phosphorylation uncoupling, and eventually programmed cell death (autophagy). b Clinical trial scheme: Dose escalation had a 3 + 3 scheme. All cohorts received the indicated daily doses in two oral administrations, except those cohorts receiving 12,000 mg/d, which were administered TID (4000 mg per dose).