Abstract 2529: The anti-malarial agent Mefloquine preferentially demonstrates pre-clinical activity in leukemia and myeloma cells through STAT1-induced reactive oxygen species production

Abstract

Abstract Off patent drugs with previously unrecognized anti-leukemia activity can be rapidly repurposed for this new indication, given their prior safety and toxicity testing. By screening a group of anti-malarial compounds for anti-cancer activity, we identified mefloquine, a quinoline licensed in oral formulation for the treatment of malaria. As an anti-cancer agent, we demonstrated that mefloquine decreased the viability of 9/9 leukemia cell lines with an LD50 <7.5 uM, and 9/9 myeloma cell lines with an LD50 <5.0 uM. Furthermore, mefloquine demonstrated induced cell death in primary AML samples (n = 3; LD50 <7.5 uM), but not normal peripheral blood stem cells. Given its in vitro activity, we evaluated the effects of oral mefloquine in mouse xenograft models of leukemia. Sublethally irradiated SCID mice were injected subcutaneously with OCI-AML2 or K562 human leukemia cells or MDAY-D2 murine leukemia cells, and treated with 50 mg/kg mefloquine, or vehicle alone by oral gavage. Oral mefloquine decreased tumor weight and volume in all 3 mouse models without toxicity. Mechanistically, mefloquine induced reactive oxygen species (ROS) in leukemia cells at times preceding and concentrations associated with cell death. Blockade of ROS by N-acetyl-L-cysteine (NAC) abrogated mefloquine sensitivity, suggesting that mefloquine-mediated cell death in AML was ROS-dependent. To further understand the mechanism of mefloquine-mediated cytoxicity, whole genome gene expression oligonucleotide array analysis of AML cells treated with mefloquine was conducted. The gene expression pattern of cells treated with mefloquine strongly resembled gene signatures associated with activated Toll-like receptor and interferon response pathways. STAT1 and NF-κB, both downstream transcription factor components of TLR-IFN signaling, were activated, as were downstream targets IRF1, IRF7 and IL-8, at times that preceded mefloquine-induced cell death. Gene expression changes were validated by Q-RT-PCR, and are potential biomarkers of mefloquine activity in cells. This pathway appears functionally important for mefloquine-mediated cell death, as cell lines defective for STAT1 signaling components showed decreased cell death after mefloquine treatment. These lines also showed decreased ability to generate ROS in response to mefloquine treatment, suggesting that mefloquine-induced ROS was produced through a STAT1-dependent mechanism. Taken together, our data demonstrate that the anti-malarial mefloquine displays significant pre-clinical activity in leukemia and myeloma cells, likely through a STAT1-dependent induction of ROS that is triggered by activation of the TLR-IFN cytokine axis in cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2529.