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Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics
Acute myeloid leukemia (AML) is a neoplastic disorder resulting from clonal proliferation of poorly differentiated immature myeloid cells. Distinct genetic and epigenetic aberrations are key features of AML that account for its variable response to standard therapy. Irrespective of their oncogenic m...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749238/ https://www.ncbi.nlm.nih.gov/pubmed/31466259 http://dx.doi.org/10.3390/molecules24173121 |
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author | Lee, Michelle H. Lapidus, Rena G. Ferraris, Dana Emadi, Ashkan |
author_facet | Lee, Michelle H. Lapidus, Rena G. Ferraris, Dana Emadi, Ashkan |
author_sort | Lee, Michelle H. |
collection | PubMed |
description | Acute myeloid leukemia (AML) is a neoplastic disorder resulting from clonal proliferation of poorly differentiated immature myeloid cells. Distinct genetic and epigenetic aberrations are key features of AML that account for its variable response to standard therapy. Irrespective of their oncogenic mutations, AML cells produce elevated levels of reactive oxygen species (ROS). They also alter expression and activity of antioxidant enzymes to promote cell proliferation and survival. Subsequently, selective targeting of redox homeostasis in a molecularly heterogeneous disease, such as AML, has been an appealing approach in the development of novel anti-leukemic chemotherapeutics. Naphthoquinones are able to undergo redox cycling and generate ROS in cancer cells, which have made them excellent candidates for testing against AML cells. In addition to inducing oxidative imbalance in AML cells, depending on their structure, naphthoquinones negatively affect other cellular apparatus causing neoplastic cell death. Here we provide an overview of the anti-AML activities of naphthoquinone derivatives, as well as analysis of their mechanism of action, including induction of reduction-oxidation imbalance, alteration in mitochondrial transmembrane potential, Bcl-2 modulation, initiation of DNA damage, and modulation of MAPK and STAT3 activity, alterations in the unfolded protein response and translocation of FOX-related transcription factors to the nucleus. |
format | Online Article Text |
id | pubmed-6749238 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-67492382019-09-27 Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics Lee, Michelle H. Lapidus, Rena G. Ferraris, Dana Emadi, Ashkan Molecules Article Acute myeloid leukemia (AML) is a neoplastic disorder resulting from clonal proliferation of poorly differentiated immature myeloid cells. Distinct genetic and epigenetic aberrations are key features of AML that account for its variable response to standard therapy. Irrespective of their oncogenic mutations, AML cells produce elevated levels of reactive oxygen species (ROS). They also alter expression and activity of antioxidant enzymes to promote cell proliferation and survival. Subsequently, selective targeting of redox homeostasis in a molecularly heterogeneous disease, such as AML, has been an appealing approach in the development of novel anti-leukemic chemotherapeutics. Naphthoquinones are able to undergo redox cycling and generate ROS in cancer cells, which have made them excellent candidates for testing against AML cells. In addition to inducing oxidative imbalance in AML cells, depending on their structure, naphthoquinones negatively affect other cellular apparatus causing neoplastic cell death. Here we provide an overview of the anti-AML activities of naphthoquinone derivatives, as well as analysis of their mechanism of action, including induction of reduction-oxidation imbalance, alteration in mitochondrial transmembrane potential, Bcl-2 modulation, initiation of DNA damage, and modulation of MAPK and STAT3 activity, alterations in the unfolded protein response and translocation of FOX-related transcription factors to the nucleus. MDPI 2019-08-28 /pmc/articles/PMC6749238/ /pubmed/31466259 http://dx.doi.org/10.3390/molecules24173121 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lee, Michelle H. Lapidus, Rena G. Ferraris, Dana Emadi, Ashkan Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics |
title | Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics |
title_full | Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics |
title_fullStr | Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics |
title_full_unstemmed | Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics |
title_short | Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics |
title_sort | analysis of the mechanisms of action of naphthoquinone-based anti-acute myeloid leukemia chemotherapeutics |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749238/ https://www.ncbi.nlm.nih.gov/pubmed/31466259 http://dx.doi.org/10.3390/molecules24173121 |
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