Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics

Abstract

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.

Oxidative Stress and ROS-Mediated Signaling in Leukemia: Novel Promising Perspectives to Eradicate Chemoresistant Cells in Myeloid Leukemia

“…At low levels, under normal and physiological conditions when the balance between ROS production and detoxification is assured, ROS contribute to regulate a large variety of normal cellular functions including proliferation, differentiation, epigenetic modification and quiescence. On the other hand, altered ROS homeostasis has detrimental effects caused by protein, lipid and DNA damage and subsequent disruption of cell functions [ 1 , 2 ]. Therefore, in place of the general term of oxidative stress (OS) comprising all conditions caused by over-burdened and/or disabled antioxidant systems leading to altered redox status, two recent neologisms have been coined to distinguish eustress states as those referring to physiological low oxidative stress conditions involved in redox signaling (ROS low status) from oxidative distress caused by impaired ROS homeostasis leading to disrupted redox signaling and/or oxidative damage to biomolecules (ROS high status) [ 3 ].…”

Heterocycles in Medicinal Chemistry

“…A publication on pharmacological topics presents both the search for mechanisms of actions of naphthoquinone-based chemotherapeutics active against acute myeloid leukemia [10] and studies evaluating cryptopleurine (thienoquinolizidine derivatives and (epi-)benzo analogues) phenanthroquinolizidine alkaloids inducing cell death of leukemia cells [11].…”

Synthesis, Characterization and Apoptosis Capabilities of a Novel Naphthoquinone‐Derived Compound in Triple‐Negative Breast Cancer

“…In the MDA‐MB‐231 cell line, the ZP‐2 compound raises the level of intracellular ROS. It is well known that compounds derived from NQ raised the level of ROS by elevating semiquinone and hydroquinone, and several studies showed that compounds derived from NQ raised the level of ROS in various cancer cell lines [15–17] . The Muse kit that determined the ROS level can only measure the superoxide level from reactive oxygen derivatives.…”

“…It is well known that compounds derived from NQ raised the level of ROS by elevating semiquinone and hydroquinone, and several studies showed that compounds derived from NQ raised the level of ROS in various cancer cell lines. [15][16][17] The Muse kit that determined the ROS level can only measure the superoxide level from reactive oxygen derivatives. The ZP-2 compound can raise superoxide and intracellular ROS levels; at various doses and/or times, other ROS levels may also be raised by this substance.…”