Doxorubicin Redox Biology: Redox Cycling, Topoisomerase Inhibition, and Oxidative Stress

Zhu, Hong; Sarkar, Soumyadeep; Scott, Laura J.; Danelisen, Igor; Trush, Michael A.; Jia, Zhenquan; Li, Y. Robert

doi:10.20455/ros.2016.835

Cited by 93 publications

(73 citation statements)

References 35 publications

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“…This observation has important implications in using MitoSOX assays to detect the ROS formation induced by doxorubicin. In this context, doxorubicin is widely viewed as a redox cycling quinone to produce ROS in biological systems though recent evidence does not support this notion [5]. …”

Section: Resultsmentioning

confidence: 99%

“…The mechanisms of action of doxorubicin regarding both tumor killing and adverse effects remain partially understood. It is partly for this reason that doxorubicin is currently among the most extensively studied anticancer drugs in the fields of both basic biomedical research and clinical medicine [5]. In this context, determination of the cellular dynamics of doxorubicin is of crucial importance in understanding its cellular effects in both cancer and normal cells.…”

Section: Introductionmentioning

confidence: 99%

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Fluorescence-Based Assays for Measuring Doxorubicin in Biological Systems

Kauffman

Zhu

et al. 2016

ROS

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Detection and measurement of doxorubicin in biological systems, including body fluids, cells, and tissues, are instrumental in understanding the mechanisms of action of this widely used drug in treating cancer as well as in causing adverse effects. In this article, we, for the first time, characterized the use of fluorescence-based techniques, including fluorescence spectrometry, microscopy, and flow cytometry in measuring and/or detecting doxorubicin in biological systems, including cell lysates and cultured intact cells. We showed that doxorubicin has a maximum excitation and emission wavelength of 470 and 560 nm, respectively. The detection sensitivity by fluorescence spectrometry is less than 0.1 μM in buffers and cell lysates. Fluorescence microscopy demonstrated the readily detection of concentration-dependent accumulation of doxorubicin in cultured cells via either green or red fluorescence, but with green fluorescence showing a higher sensitivity of detection. Flow cytometry also revealed sensitive detection of doxorubicin accumulation in cell suspensions in a concentration-dependent manner. The readily and sensitive measurement and detection of doxorubicin by the above three fluorescence-based techniques has important implications in studying the cellular dynamics of doxorubicin in both cancer and normal cells under various experimental conditions.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fluorescence-Based Assays for Measuring Doxorubicin in Biological Systems

Kauffman

Zhu

et al. 2016

ROS

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“…The stabilization of the cleavage complex impedes DNA resealing, resulting in double‐stranded DNA breaks. When bound to TOP2α, the complex inhibits DNA replication and induces apoptosis as intended in proliferating malignant cells . Damage to non‐proliferating, quiescent cells, like the heart muscle, where TOP2β is the major form, results in heart muscle failure as a side effect …”

Section: Anticancer Mechanism Of Anthracyclinesmentioning

confidence: 99%

“…Without TOP2ß, DOX cannot bind directly to DNA, protecting the cardiomyocytes against DNA double‐strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and increased ROS accumulation. When bound to TOP2ß, mitochondrial dysfunction is triggered by the suppression of peroxisome proliferator‐activated receptor (PPAR), which regulates oxidative metabolism, in adult mammalian cardiomyocytes …”

Section: Doxorubicin‐induced Cardiotoxicitymentioning

confidence: 99%

Update on pathophysiology and preventive strategies of anthracycline‐induced cardiotoxicity

Corremans

Adão

Keulenaer

et al. 2018

Clin Exp Pharma Physio

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Summary Anthracycline chemotherapy has a prominent role in treating many forms of cancer. Unfortunately, cardiotoxic side effects represent a serious limitation to their use, with doxorubicin being the leading drug of the group. Indeed, anthracycline‐induced cardiomyopathy is an important public health concern because it may not be detected for many years and remains a lifelong threat. Even after decades of investigation, neither the exact mode of action of anthracyclines nor the pathways leading to their side effect are fully understood. It is increasingly important to establish collaboration between oncologists and cardiologists to improve the management of cancer patient receiving anthracyclines. This article reviews the clinical course, pathogenesis, cardiac monitoring and new concepts in diagnosing and preventing anthracycline‐induced cardiotoxicity.

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“…C, Western blots and relative levels of SOD2 in H9C2 cardiomyoblasts with the same treatment as in A. D, Western blots and relative levels of Bcl-2 in H9C2 cardiomyoblasts with the same treatment as in A. E, Western blots and relative levels of Bax in H9C2 cardiomyoblasts with the same treatment as in A. F, Western blots and relative levels of cleaved caspase-3 in H9C2 cardiomyoblasts with the same treatment as in A (n = 5 individual experiments, * P < 0.05, ** P < 0.01 vs vehicle of control siRNA; ## P < 0.01 vs control siRNA with acacetin)oxygen species (ROS) and maintain redox homeostasis 26. ROS, that is, peroxides, superoxide, hydroxyl radical and singlet oxygen, are produced intracellularly through multiple mechanisms depending on the cell and tissue types in cell membranes, mitochondria, peroxisomes and endoplasmic reticulum.…”

mentioning

confidence: 99%

Doxorubicin cardiomyopathy is ameliorated by acacetin via Sirt1‐mediated activation of AMPK/Nrf2 signal molecules

Cui

Hong

et al. 2020

J Cellular Molecular Medi

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Doxorubicin is an anthracycline chemotherapy drug widely used in clinic for treating breast, endometrial and gastric cancers, childhood solid tumours, soft tissue sarcomas and aggressive lymphoblastic or myeloblastic leukaemia. 1,2 However, dilated cardiomyopathy and congestive heart failure are frequently reported in patients treated with doxorubicin. Mortality and morbidity are therefore increased when heart failure develops in these patients. 3,4 Dexrazoxane is the only FDA-approved drug that is used to protect against doxorubicin-induced cardiomyopathy, 5 but it carries the risk potential of increasing secondary malignant neoplasms. 6 Betaadrenoceptor blockers, angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers are reported to be effective in preventing anthracycline-induced cardiotoxicity 5 ; however, the reports from different observations are controversial. 7 Therefore, new avenues of exploration are needed to develop better pharmacotherapies and interventions to prevent the cardiotoxicity. 8 It has been reported that several mechanisms are involved in cardiomyopathy induced by doxorubicin, including oxidative stress,

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Doxorubicin Redox Biology: Redox Cycling, Topoisomerase Inhibition, and Oxidative Stress

Cited by 93 publications

References 35 publications

Fluorescence-Based Assays for Measuring Doxorubicin in Biological Systems

Fluorescence-Based Assays for Measuring Doxorubicin in Biological Systems

Update on pathophysiology and preventive strategies of anthracycline‐induced cardiotoxicity

Doxorubicin cardiomyopathy is ameliorated by acacetin via Sirt1‐mediated activation of AMPK/Nrf2 signal molecules

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