5-Lipoxygenase: Its Noncanonical Function Unravels its Inhibitors as Powerful Antileukemic Drugs

Besides its function as key enzyme in the biosynthesis of leukotrienes (Figure 1), there is accumulating evidence that 5-lipoxygenase (5-LO) has additional, noncanonical functions. The enzyme is mainly expressed in leukocytes. After stimulation of neutrophils, the enzyme is activated by an increase in intracellular calcium concentration and by phosphorylation by 5-LO kinases. Leukotrienes are considered as proinflammatory mediators which are involved in host defense reactions and which contribute to allergic and inflammatory reactions (1). Zileuton (Figure 2) is the only approved 5-LO inhibitor, which binds to the iron ion in the active cite. Cys-LT1 receptor antagonists which block the action of LTC4 and its metabolites in the lung are approved for the treatment of asthma and allergic rhinitis. Expression of the enzyme is regulated in a cell cycle and cell differentiationdependent manner (2). It is a TGF-β and vitamin D response gene which seems to be controlled by transcription factors that regulate stemness, lineage-specific differentiation of myeloid and lymphocytic cells including p53, SMAD1, C/EBPα, GATA2, PU.1, RUNX1, RUNX3 and the WNT pathway (3). Aberrant 5-LO expression is observed in many cancer tissues and cells which suggested that the 5-LO pathway might be involved in cancer development (for review see (4)). A clear evidence for the role of 5-LO in cancer came from the observation that 5-LO knockout prevents the development of chronic myeloid leukemia in a murine BCR/ABL leukemia model (5). Interestingly, 5-LO knockout does not seem to lead to a defect in normal hematopoiesis. First mechanistic insights into the role of 5-LO came from the observation that 5-LO alters nuclear trafficking of p53 and leads to inhibition of apoptosis (6).