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Pharmaceuticals 2016, 9(1), 4; doi:10.3390/ph9010004

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

1
Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
2
Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
3
Center for Biomolecular Therapeutics, School of Medicine, University of Maryland, Baltimore, MD 20850, USA
4
Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
5
Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
6
Department of Radiation Oncology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
7
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Dhimant Desai
Received: 30 November 2015 / Revised: 7 January 2016 / Accepted: 14 January 2016 / Published: 19 January 2016
(This article belongs to the Special Issue Chemotherapeutic Agents)
View Full-Text   |   Download PDF [2602 KB, uploaded 19 January 2016]   |  

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. View Full-Text
Keywords: dimeric naphthoquinone; acute myeloid leukemia (AML); oxidative stress; reactive oxygen species (ROS) dimeric naphthoquinone; acute myeloid leukemia (AML); oxidative stress; reactive oxygen species (ROS)
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MDPI and ACS Style

Lapidus, R.G.; Carter-Cooper, B.A.; Sadowska, M.; Choi, E.Y.; Wonodi, O.; Muvarak, N.; Natarajan, K.; Pidugu, L.S.; Jaiswal, A.; Toth, E.A.; Rassool, F.V.; Etemadi, A.; Sausville, E.A.; Baer, M.R.; Emadi, A. 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. Pharmaceuticals 2016, 9, 4.

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