WRC-213, an l-methionine-conjugated mitoxantrone derivative, displays anticancer activity with reduced cardiotoxicity and drug resistance: Identification of topoisomerase II inhibition and apoptotic machinery in prostate cancers

Hsiao, Chiaolong; Li, Tsia-Kun; Chan, Ya-Ling; Hsin, Ling‐Wei; Liao, Chen; Lee, Chien-Hua; Lyu, Ping‐Chiang; Guh, Jih‐Hwa

doi:10.1016/j.bcp.2007.10.012

Cited by 36 publications

(19 citation statements)

References 31 publications

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“…ETO is used mainly in the treatment of refractory testicular tumors and for the treatment of small-cell lung carcinoma and has been associated with hypotension [18]. In vitro, Hsiao et al demonstrated that 10 μM of ETO inhibited the cell growth of H9c2 cardiomyoblasts by 55% [19][20][21]. In our study, ETO decreased the cell viability of H9c2 cardiomyoblasts in a dose dependent manner with a greater decrease in cell viability with increasing concentrations of ETO.…”

Section: Discussionmentioning

confidence: 59%

The Efficacy of Etoposide on H9c2 Cardiomyoblasts Against Doxorubicin Induced Cardiotoxicity

Shabana¹,

Aden²,

Abdulrahman³

et al. 2015

Anat Physiol

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A n at omy & P h y s io logy: C u r r e n t Re sear c h ISSN: 2161-0940 Shabana et al., Anat Physiol 2015, 5:4 http://dx.doi.org/10.4172/2161 Keywords: Doxorubicin; Etoposide; Topoisomerase II; Cardiomyocyte hypertrophy Introduction Doxorubicin (DOX), one of the most effective and used anthracyclines [1], has been used for several decades due to its potent broads spectrum antineoplastic activity [2]. DOX is heavily used to treat hematological malignancies such as multiple myeloma and hodgkin's lymphoma [3,4]. In addition, DOX has been used for the treatment of solid tumors like ovarian and breast cancer [5,6]. Despite the clinical application of DOX, it is well known to induce a dose-dependent cardiotoxicity, which limits its clinical usage [7]. DOX induced cardiotoxicity, early-onset or late onset, is characterized by a decline in left ventricular ejection fraction or the development of congestive heart failure [1]. In a retrospective analysis of three trials it has been demonstrated that 26% of all patients who receive a cumulative DOX dose of ≥ 550 mg/m2 develop DOX related congestive heart failure [8].The underlying molecular mechanism of DOX induced cardiotoxicity remains unclear. Zhang et al. reported that chronic DOX exposure induces functional and structural changes in the mitochondria; manifested by mitochondrial damage and vacuolization [9]. In addition, DOX was found to induce alterations in cardiac myosin and is responsible for nuclear membrane disruption [10]. Previous reports have associated DOX induced cardiotoxicity with its ability to produce reactive oxygen species (ROS) [11,12], which causes a release of iron and contributes to DNA damage and lipid peroxidation [13]. Recent reports have suggested that DOX-induced cardiotoxicity is mediated in part by topoisomerase II (TOPII) -β expression and activity [9,13,14]. TOPII is an enzyme that uncoils the supercoiled double stranded DNA and contributes to DNA replication. Two isoforms of TOPII exist, TOPII-a and TOPII-β, which are expressed in different tissue. TOPII-a is expressed in proliferating tissues including the bone marrow, spleen, and tumor cells and TOPII-β is expressed in adult mammalian cardiomyocytes [15]. Furthermore, an in vitro study showed that Dexrazoxane, which is the only approved iron-chelating agent to treat DOX induced cardiotoxicity, reduced the expression of TOPII-β enzyme [14]. Another study demonstrated that TOPII-β knockout mice had improved cardiac function compared to the control group [9]. In our study, we hypothesize that TOPII-β contributes to DOX induced cardiotoxicity.In our study we aimed to develop an in-vitro model in which DOX induces cardiotoxicity. In addition, we investigated the effect of inhibiting TOPII in attenuating DOX induced cardiotoxicity. Etoposide (ETO), a non-specific TOPII targeted anticancer drug and used in solid tumors such as lung cancer, lymphomas and sarcomas, was used in our study to inhibit TOPII [16]. Zhang et al. reported that ETO possess a time dependent degradation of both TOPII-a an...

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Section: Discussionmentioning

confidence: 59%

The Efficacy of Etoposide on H9c2 Cardiomyoblasts Against Doxorubicin Induced Cardiotoxicity

Shabana¹,

Aden²,

Abdulrahman³

et al. 2015

Anat Physiol

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“…WRC-213 induces the comettail formation in DNA of fewer cells (indicating less genotoxicity), as well as lower cytotoxicity than MTX in H9c2 cells. The authors suggested that the population-doubling time of H9c2, which is about twofold lower than that of cancer cells, is a determining factor of the less WRC-213 toxicity in cardiac cells (Hsiao et al 2008). If this hypothesis, however, was true, MTX should have shown less cardiotoxicity as well, which was not observed.…”

Section: Topoisomerase Inhibitionmentioning

confidence: 90%

Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone

et al. 2016

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Anthracyclines, e.g., doxorubicin (DOX), and anthracenediones, e.g., mitoxantrone (MTX), are drugs used in the chemotherapy of several cancer types, including solid and non-solid malignancies such as breast cancer, leukemia, lymphomas, and sarcomas. Although they are effective in tumor therapy, treatment with these two drugs may lead to side effects such as arrhythmia and heart failure. At the same clinically equivalent dose, MTX causes slightly reduced cardiotoxicity compared with DOX. These drugs interact with iron to generate reactive oxygen species (ROS), target topoisomerase 2 (Top2), and impair mitochondria. These are some of the mechanisms through which these drugs induce late cardiomyopathy. In this review, we compare the cardiotoxicities of these two chemotherapeutic drugs, DOX and MTX. As described here, even though they share similarities in their modes of toxicant action, DOX and MTX seem to differ in a key aspect. DOX is a more redox-interfering drug, while MTX induces energy imbalance. In addition, DOX toxicity can be explained by underlying mechanisms that include targeting of Top2 beta, mitochondrial impairment, and increases in ROS generation. These modes of action have not yet been demonstrated for MTX, and this knowledge gap needs to be filled.

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“…It is known that hydroxy-anthraquinones containing a poly-aromatic ring structure can bind to DNA by intercalation and stacking between the base pairs of DNA double helices (20). Given these properties, hydroxyanthraquinones represent promising anticancer agents.…”

Section: Resultsmentioning

confidence: 99%

“…All of this seemingly overwhelming evidence has shaped the concept of hydroxyanthraquinones as antineoplastic agents and several mechanisms have been proposed regarding their anticancer activity. One refers to the ability of the drug to intercalate DNA (20) and inhibit DNA topoisomerase II (24). Another refers to the ability of the drug to produce free radicals and consequently to cleave DNA (25).…”

Section: Resultsmentioning

confidence: 99%

Evaluation of natural anthracene-derived compounds as antimitotic agents

Badria

Ibrahim

2013

Drug Discov Ther

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Plants that contain anthracenederived compounds such as anthraquinones have been reported to act as anticancer besides their use for millennia to treat constipation, but the mechanism of action is still unfolding. Therefore we pursue this study to explore a new horizon in the anticancer property of these agents with relevance to mitotic arrest. To achieve this goal, the antimitotic activity of a series of naturally occurring anthracene-derived anthraquinones including anthrone, alizarin (1,2-dihydroxyanthraquinone), quinizarin (1,4-dihydroxyanthraquinone), rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid), emodin (1,6,8-trihydroxy-3-methyl-anthraquinone), and aloe emodin (1,8 dihydroxy-3-hydroxymethyl anthraquinone) were evaluated using Allium cepa root tips. Initial results revealed that the mitosis was inhibited after 3, 6, and 24 h, respectively, of incubation with 500, 250, and 125 ppm of each compound in a dose-dependent manner. Furthermore, alizarin at 500 ppm was proved to be the most active compound to arrest the mitosis after 24 h followed by emodin, aloe emodin, rhein, and finally quinizarin. Interestingly, this inhibition of mitosis was irreversible in root tips incubated with each compound at concentration of 500 ppm but not with 250 ppm or 125 ppm, where the roots regained their normal mitotic activity after 96 h post-incubation in water. This re-evaluation of an old remedy suggests that several bioactive anthraquinones possess promising anti-mitotic activity that may have the potential to be lead compounds for the development of a new class of multifaceted natural anticancer/antimitotic agents.

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WRC-213, an l-methionine-conjugated mitoxantrone derivative, displays anticancer activity with reduced cardiotoxicity and drug resistance: Identification of topoisomerase II inhibition and apoptotic machinery in prostate cancers

Cited by 36 publications

References 31 publications

The Efficacy of Etoposide on H9c2 Cardiomyoblasts Against Doxorubicin Induced Cardiotoxicity

The Efficacy of Etoposide on H9c2 Cardiomyoblasts Against Doxorubicin Induced Cardiotoxicity

Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone

Evaluation of natural anthracene-derived compounds as antimitotic agents

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