Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 29 November 2021 / Approved: 30 November 2021 / Online: 30 November 2021 (21:37:18 CET)

How to cite: Dakik, H.; El Dor, M.; Bourgeais, J.; Kouzi, F.; Herault, O.; Gouilleux, F.; Zibara, K.; Mazurier, F. Diphenyleneiodonium Triggers Cell Death of Acute Myeloid Leukaemia Cells by Blocking the Mitochondrial Respiratory Chain and Synergizes with Cytarabine. Preprints 2021, 2021110578 (doi: 10.20944/preprints202111.0578.v1). Dakik, H.; El Dor, M.; Bourgeais, J.; Kouzi, F.; Herault, O.; Gouilleux, F.; Zibara, K.; Mazurier, F. Diphenyleneiodonium Triggers Cell Death of Acute Myeloid Leukaemia Cells by Blocking the Mitochondrial Respiratory Chain and Synergizes with Cytarabine. Preprints 2021, 2021110578 (doi: 10.20944/preprints202111.0578.v1).

Abstract

Acute myeloid leukaemia (AML) is characterized by the accumulation of undifferentiated blast cells in the bone marrow and blood. In most AMLs, 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 triggered an increase in the mitochondrial ROS levels caused by the disruption of the mitochondrial respiratory chain. We also demonstrated that DPI blocks the mitochondrial oxidative respiration (OxPhos) in a dose-dependent manner and that AML cells with high OxPhos status were highly sensitive to treatment with DPI, which synergizes with the chemotherapeutic agent cytarabine (Ara-C). Thus, our results suggest that targeting mitochondrial function by DPI might be exploited to target AML cells with high OxPhos status.

Keywords

DPI; Mitochondria; Leukaemia; Oxidative stress; OxPhos; Ara-C

Subject

MEDICINE & PHARMACOLOGY, Other

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