Diphenyleneiodonium Triggers Cell Death of Acute Myeloid Leukemia Cells by Blocking the Mitochondrial Respiratory Chain, and Synergizes with Cytarabine

SIMPLE SUMMARY: Acute myeloid leukemia (AML) is an aggressive heterogeneous cancer of the blood, of which 70% of cases develop relapse. Relapse is mainly due to chemoresistant leukemic cells (LCs) that are characterized by high mitochondrial oxidative phosphorylation (OxPhos) status, i.e., cells that are dependent on the mitochondrial respiratory chain (MRC) function. The aim of our study was to determine whether diphenyleneiodonium (DPI)—known as a potent inhibitor of flavoproteins—could be used to target AML cells. Herein, we demonstrate that DPI disrupts the mitochondrial function of AML cell lines. Interestingly, we found that cells with high OxPhos are more sensitive to the apoptotic effects of DPI. Moreover, we showed that DPI sensitizes AML cell lines to cytarabine (Ara-C) treatment, suggesting that MRC inhibitors could be employed to target LCs that are resistant to this chemotherapeutic agent. ABSTRACT: Acute myeloid leukemia (AML) is characterized by the accumulation of undifferentiated blast cells in the bone marrow and blood. In most cases of AML, relapse frequently occurs due to resistance to chemotherapy. Compelling research results indicate that drug resistance in cancer cells is highly dependent on the intracellular levels of reactive oxygen species (ROS). Modulating ROS levels is therefore a valuable strategy to overcome the chemotherapy resistance of leukemic cells. In this study, we evaluated the efficiency of diphenyleneiodonium (DPI)—a well-known inhibitor of ROS production—in targeting AML cells. Results showed that although inhibiting cytoplasmic ROS production, DPI also triggered an increase in the mitochondrial ROS levels, caused by the disruption of the mitochondrial respiratory chain. We also demonstrated that DPI blocks mitochondrial oxidative phosphorylation (OxPhos) in a dose-dependent manner, and that AML cells with high OxPhos status are highly sensitive to treatment with DPI, which synergizes with the chemotherapeutic agent cytarabine (Ara-C). Thus, our results suggest that targeting mitochondrial function with DPI might be exploited to target AML cells with high OxPhos status.