5-Lipoxygenase Is a Candidate Target for Therapeutic Management of Stem Cell–like Cells in Acute Myeloid Leukemia

Abstract

Nonsteroidal anti-inflammatory drugs such as sulindac inhibit Wnt signaling, which is critical to maintain cancer stem cell-like cells (CSC), but they also suppress the activity of 5-lipoxygenase (5-LO) at clinically feasible concentrations. Recently, 5-LO was shown to be critical to maintain CSC in a model of chronic myeloid leukemia. For these reasons, we hypothesized that 5-LO may offer a therapeutic target to improve the management of acute myeloid leukemia (AML), an aggressive disease driven by CSCs. Pharmacologic and genetic approaches were used to evaluate the effects of 5-LO blockade in a PML/RARa-positive model of AML. As CSC models, we used Sca-1 þ /lin À murine hematopoietic stem and progenitor cells (HSPC), which were retrovirally transduced with PML/RARa. We found that pharmacologic inhibition of 5-LO interfered strongly with the aberrant stem cell capacity of PML/RARa-expressing HSPCs. Through small-molecule inhibitor studies and genetic disruption of 5-LO, we also found that Wnt and CSC inhibition is mediated by the enzymatically inactive form of 5-LO, which hinders nuclear translocation of b-catenin. Overall, our findings revealed that 5-LO inhibitors also inhibit Wnt signaling, not due to the interruption of 5-LO-mediated lipid signaling but rather due to the generation of a catalytically inactive form of 5-LO, which assumes a new function. Given the evidence that CSCs mediate AML relapse after remission, eradication of CSCs in this setting by 5-LO inhibition may offer a new clinical approach for immediate evaluation in patients with AML. Cancer Res; 74(18); 5244-55. Ó2014 AACR.

Cross-Talk between Cancer Cells and the Tumour Microenvironment: The Role of the 5-Lipoxygenase Pathway

“…The 5-LO pathway is not just relevant to solid malignancies as there has been recent evidence demonstrating the utility of 5-LO inhibition as a clinical approach for cancer-stem-cell driven acute myeloid leukemia [80]. Genetic or pharmacological inhibition of 5-LO in disease models, rendered the enzyme inactive and had the knock-on effect of suppressing Wnt signalling, a process critical for maintenance of the cancer stem cell population.…”

Apoptotic Cancer Cells Suppress 5-Lipoxygenase in Tumor-Associated Macrophages

“…Aberrant formation of 5-LO metabolites is therefore tightly associated with several diseases such as asthma, arthritis, atherosclerosis, Alzheimer's disease, and type 2 diabetes (3)(4)(5)(6). Moreover, enhanced expression of 5-LO and 5-LO product formation is found in several types of cancer such as breast (7), prostate (8,9), pancreatic (10,11), and colon (12), as well as in cancer stem celldriven acute myeloid leukemia (13). Functionally, 5-LO products increase cellular proliferation and suppress cancer cell apoptosis.…”

Myxochelins Target Human 5-Lipoxygenase

“…20 The enzyme 5-LO was shown to be critically involved in chronic myeloid leukemia and was proposed to be a candidate target for therapeutic management of stem-cell-like cells in acute myeloid leukemia. 21,22 Similarly, mPGES-1 inhibitors were proposed to be promising candidates for leukemia treatment. 23 Therefore, inhibition of 5-LO and/or mPGES-1 could provide a plausible explanation for the marked antiproliferative effects of myxochelin A in K-562 cells, in particular since various 5-LO inhibitors were found to induce cell death of K-562 cells.…”