Inhibitors and Poisons of Mammalian Type II Topoisomerases

Murphy, Matthew B.; Mercer, Susan L.; Deweese, Joseph E.

doi:10.1016/b978-0-12-812522-9.00005-1

Cited by 31 publications

(55 citation statements)

References 148 publications

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“…There are catalytic inhibitors of human type-II topoisomerases that block enzyme functions without stabilizing DNA cleavage. 14,27,28 These often involve interactions with the ATPase domain, but they are not necessarily limited to that mechanism. Additional studies of gemifloxacin will be required to determine the mechanism behind the inhibition of human topoisomerase IIα and IIβ.…”

Section: Resultsmentioning

confidence: 99%

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Examining the Impact of Antimicrobial Fluoroquinolones on Human DNA Topoisomerase IIα and IIβ

et al. 2019

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Fluoroquinolones are a class of widely prescribed antibiotics with a broad range of activity against Gram-positive, Gram-negative, and some atypical microbes. Unfortunately, these drugs are associated with significant adverse events including neuropathy, tendinopathy, cardiac rhythm abnormalities, and mental health side effects. The mechanism by which fluoroquinolones cause many of these toxicities is unknown. The antibacterial mechanism of action involves disruption of the catalytic mechanism of type-II topoisomerases in bacteria, namely topoisomerase IV and DNA gyrase. Fluoroquinolones inhibit the ability of the enzymes to ligate cleaved DNA and result in single- and double-stranded DNA breaks. Thus, there is an interest in investigating whether human topoisomerase II is involved in mediating the adverse events associated with quinolones. Previous studies demonstrate some response of human topoisomerase IIα and IIβ to high levels of ciprofloxacin. However, it is not clear whether the concentration of ciprofloxacin utilized in those studies corresponds to concentrations that would be routinely achievable in patients. Therefore, this study set out to examine three clinically relevant fluoroquinolones along with two older agents to determine whether these compounds display activity against topoisomerase IIα and IIβ at drug concentrations that more closely approximate typical patient plasma values. On the basis of our evidence, none of the quinolones studied were able to poison DNA cleavage by either human enzyme. Ciprofloxacin, desethylene-ciprofloxacin, and the recently removed from market gemifloxacin were able to inhibit topoisomerase II-mediated DNA relaxation at concentrations of 200–300 μM. On the basis of these data, we propose that human topoisomerase II is not likely to be the main cause of these adverse events and that additional targets need to be identified to clarify the mechanisms underlying quinolone toxicities.

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Section: Resultsmentioning

confidence: 99%

“…Disruption of this mechanism has been used in both antimicrobial and anticancer therapeutics. 10,14,15 Humans encode two isoforms of topoisomerase II: topoisomerase IIα and IIβ, which are known targets for anticancer agents. 13,14,16 Both isoforms are found in the nucleus and the mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Examining the Impact of Antimicrobial Fluoroquinolones on Human DNA Topoisomerase IIα and IIβ

et al. 2019

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“…The drug was approved in 1983 in Canada 25 and to date is used for the treatment patients with AML and refractory ALL. The inhibitory effect of m -AMSA on hTop IIβ activity is based on the topoisomerase poisoning and increasing level of DNA- hTop IIβ covalent complexes in the cell 190 , 191 . Furthermore, few clinical trials are conducted to evaluate the effectiveness of combination therapy ( m -AMSA with various compounds) in the treatment of several cancers (NCT03765541, NCT00003436, NCT00002719).…”

Section: Topoisomerase Inhibitorsmentioning

confidence: 99%

“…Scientists presume that by increasing the distance between Tyr-805 and the hTop IIα reaction site, merbarone prevents the 5′-phosphotyrosyl bond in the hTop IIα-DNA complex 206 . Currently, the drug is used as a tool for studies on Top II 191 .…”

Section: Topoisomerase Inhibitorsmentioning

confidence: 99%

DNA topoisomerases as molecular targets for anticancer drugs

Buzun

Bielawska

Bielawski

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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The significant role of topoisomerases in the control of DNA chain topology has been confirmed in numerous research conducted worldwide. The prevalence of these enzymes, as well as the key importance of topoisomerase in the proper functioning of cells, have made them the target of many scientific studies conducted all over the world. This article is a comprehensive review of knowledge about topoisomerases and their inhibitors collected over the years. Studies on the structure-activity relationship and molecular docking are one of the key elements driving drug development. In addition to information on molecular targets, this article contains details on the structure-activity relationship of described classes of compounds. Moreover, the work also includes details about the structure of the compounds that drive the mode of action of topoisomerase inhibitors. Finally, selected topoisomerases inhibitors at the stage of clinical trials and their potential application in the chemotherapy of various cancers are described.

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“…Disruption of TOP2 function leads to cell death, and several anticancer agents, such as etoposide and the anthracyclines like doxorubicin, target TOP2 in order to kill cancer cells (Deweese and Osheroff 2009 ). The most common way TOP2 agents affect TOP2 is by stabilizing increased DNA strand breaks through a mechanism known as poisoning (Murphy et al 2017 ). Etoposide and the anthracyclines are considered TOP2 poisons.…”

Section: Introductionmentioning

confidence: 99%

Cannabidiol oxidation product HU-331 is a potential anticancer cannabinoid-quinone: a narrative review

2021

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Cannabidiol and related cannabinoids are under exploration for the treatment of a number of disease states. The cannabinoid-quinone HU-331 has been studied as a potential anticancer therapeutic. Previous studies provide evidence that HU-331 displays anticancer activity without some of the known adverse events associated with traditional anticancer agents. In this brief review, we will explore the literature related to the activity of HU-331 in purified systems, cancer cell lines, and animal models. For example, HU-331 displays inhibitory activity against human topoisomerase IIα, a known anticancer drug target. Further, in multiple cell model systems, the IC50 value for HU-331 was less than 10 μM. In addition, mouse model systems demonstrate the ability of HU-331 to shrink tumors without causing cardiotoxicity. In addition, we will briefly review the activity of some key analogs and derivatives of HU-331 for various disease states. Taken together, the published studies support further exploration of HU-331 for the treatment of cancer and possibly other disease states.

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Inhibitors and Poisons of Mammalian Type II Topoisomerases

Cited by 31 publications

References 148 publications

Examining the Impact of Antimicrobial Fluoroquinolones on Human DNA Topoisomerase IIα and IIβ

Examining the Impact of Antimicrobial Fluoroquinolones on Human DNA Topoisomerase IIα and IIβ

DNA topoisomerases as molecular targets for anticancer drugs

Cannabidiol oxidation product HU-331 is a potential anticancer cannabinoid-quinone: a narrative review

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