title: Hydroxylated Dimeric Naphthoquinones Increase the Generation of Reactive Oxygen Species, Induce Apoptosis of Acute Myeloid Leukemia Cells and Are Not Substrates of the Multidrug Resistance Proteins ABCB1 and ABCG2.
abstract: Selective targeting of the oxidative state, which is a tightly balanced fundamental cellular property, is an attractive strategy for developing novel anti-leukemic chemotherapeutics with potential applications in the treatment of acute myeloid leukemia (AML), a molecularly heterogeneous disease. Dimeric naphthoquinones (BiQs) with the ability to undergo redox cycling and to generate reactive oxygen species (ROS) in cancer cells are a novel class of compounds with unique characteristics that make them excellent candidates to be tested against AML cells. We evaluated the effect of two BiQ analogues and one monomeric naphthoquinone in AML cell lines and primary cells from patients. All compounds possess one halogen and one hydroxyl group on the quinone cores. Dimeric, but not monomeric, naphthoquinones demonstrated significant anti-AML activity in the cell lines and primary cells from patients with favorable therapeutic index compared to normal hematopoietic cells. BiQ-1 effectively inhibited clonogenicity and induced apoptosis as measured by Western blotting and Annexin V staining and mitochondrial membrane depolarization by flow cytometry. BiQ-1 significantly enhances intracellular ROS levels in AML cells and upregulates expression of key anti-oxidant protein, Nrf2. Notably, systemic exposure to BiQ-1 was well tolerated in mice. In conclusion, we propose that BiQ-induced therapeutic augmentation of ROS in AML cells with dysregulation of antioxidants kill leukemic cells while normal cells remain relatively intact. Further studies are warranted to better understand this class of potential chemotherapeutics.
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. RLapidus@som.umaryland.edu.|Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. RLapidus@som.umaryland.edu.
authors.forename: Rena G
authors.initials: RG
authors.lastname: Lapidus
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. bcooper@som.umaryland.edu.
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Carter-Cooper
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. mariolas349@gmail.com.
authors.forename: Mariola
authors.initials: M
authors.lastname: Sadowska
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. echoi@som.umaryland.edu.
authors.forename: Eun Yong
authors.initials: EY
authors.lastname: Choi
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. omasiri1@hotmail.com.
authors.forename: Omasiri
authors.initials: O
authors.lastname: Wonodi
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. nmuvarak@som.umaryland.edu.
authors.forename: Nidal
authors.initials: N
authors.lastname: Muvarak
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. Karthika.natarajan001@gmail.com.
authors.forename: Karthika
authors.initials: K
authors.lastname: Natarajan
authors.affiliation: Center for Biomolecular Therapeutics, School of Medicine, University of Maryland, Baltimore, MD 20850, USA. lpidugu@som.umaryland.edu.
authors.forename: Lakshmi S
authors.initials: LS
authors.lastname: Pidugu
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. ajaiswal@som.umaryland.edu.|Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. ajaiswal@som.umaryland.edu.
authors.forename: Anil
authors.initials: A
authors.lastname: Jaiswal
authors.affiliation: Center for Biomolecular Therapeutics, School of Medicine, University of Maryland, Baltimore, MD 20850, USA. etoth@som.umaryland.edu.|Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. etoth@som.umaryland.edu.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Toth
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. frassool@som.umaryland.edu.|Department of Radiation Oncology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. frassool@som.umaryland.edu.
authors.forename: Feyruz V
authors.initials: FV
authors.lastname: Rassool
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. arash.etemadi@nih.gov.
authors.forename: Arash
authors.initials: A
authors.lastname: Etemadi
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. esausville@umm.edu.|Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. esausville@umm.edu.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sausville
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. mbaer@umm.edu.|Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. mbaer@umm.edu.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. aemadi@umm.edu.|Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. aemadi@umm.edu.|Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. aemadi@umm.edu.
authors.forename: Ashkan
authors.initials: A
authors.lastname: Emadi
keywords: acute myeloid leukemia (AML); dimeric naphthoquinone; oxidative stress; reactive oxygen species (ROS)