ITPP

Myo-inositol trispyrophosphate (ITPP) was developed as an allosteric effector of hemoglobin to locally increase partial oxygen pressure. ITPP binds to band 3 proteins on red blood cells and leads to a shift of the erythrocyte intracellular pH toward acidic values. This triggers a decrease in the affinity of oxygen to hemoglobin, which results in an increased release of oxygen upon tissue demand. Subsequent to this rapidly induced and long-term physicochemical effect, ITPP normalizes the tumor vasculature on downregulation of proangiogenic factors such as HIF-1a and VEGF. In addition, ITPP selectively activates the tumor suppressor PTEN in endothelial cells, thereby inhibiting signaling downstream of PI3K and subsequently normalizing the tumor vasculature.