DNA Topoisomerases as Anticancer Drug Targets: From the Laboratory to the Clinic

Holden, Joseph A.

doi:10.2174/1568011013354859

Cited by 102 publications

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“…Topoisomerases, nuclear enzymes than can change the topology of DNA [40,41], are amongst the most promising targets for inhibiting cellular proliferation. DNA topoisomerases are crucial in cellular replication; hence, they are especially attractive targets for cancer therapy.…”

Section: Topoisomerases the Initial Biomolecular Engines Of Cell Growthmentioning

confidence: 99%

“…Interaction of a drug with a DNA topoisomerase can produce a stable, cytotoxic complex that inhibits post-cleavage DNA religation processes [42]. Indeed, this mode of action has been reported as a novel mechanism for many anticancer drugs [41]. featuring Lam-D superimposed in the active site [35] Bailly et al removed topotecan from the original structure to obtain a template on which to model the drugfree covalent complexes.…”

Section: Topoisomerases the Initial Biomolecular Engines Of Cell Growthmentioning

confidence: 99%

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Recent Advances in Lamellarin Alkaloids: Isolation, Synthesis and Activity

Plá¹,

Alberício²,

Álvarez

2008

ACAMC

104

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Lamellarins are a large family of marine alkaloids with potential anticancer activity that have been isolated from diverse marine organisms, mainly ascidians and sponges. All lamellarins feature a 3,4-diarylpyrrole system. Pentacyclic lamellarins, whose polyheterocyclic system has a pyrrole core, are the most active compounds. Some of these alkaloids are potently cytotoxic to various tumor cell lines. To date, Lam-D and Lam-H have been identified as lead compounds for the inhibition of topoisomerase I and HIV-1 integrase, respectively-nuclear enzymes which are over-expressed in deregulation disorders. Moreover, these compounds have been reported for their efficacy in treatment of multi-drug resistant (MDR) tumors cells without mediated drug efflux, as well as their immunomodulatory activity and selectivity towards melanoma cell lines. This article is an overview of recent literature on lamellarins, encompassing their isolation, recent synthetic strategies for their total synthesis, the preparation of their analogs, studies on their mechanisms of action, and their structure-activity relationships (SAR).

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Section: Topoisomerases the Initial Biomolecular Engines Of Cell Growthmentioning

confidence: 99%

Section: Topoisomerases the Initial Biomolecular Engines Of Cell Growthmentioning

confidence: 99%

Recent Advances in Lamellarin Alkaloids: Isolation, Synthesis and Activity

Plá¹,

Alberício²,

Álvarez

2008

ACAMC

104

View full text Add to dashboard Cite

show abstract

“…However, conditions that increase the physiological concentration of cleavage complexes often lead to the formation of permanent double-stranded DNA breaks in the genome. When these breaks accumulate beyond threshold levels, they induce recombination events that lead to chromosomal translocations and in some cases trigger cell death pathways (8,(11)(12)(13)(14). Thus, although the ability to cleave and religate the genetic material is critical for the physiological functions of topoisomerase II, the generation of double-stranded DNA breaks by the enzyme has potentially deleterious consequences.…”

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confidence: 99%

Base Excision Repair Intermediates as Topoisomerase II Poisons

Wilstermann¹,

Osheroff²

2001

Journal of Biological Chemistry

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Abasic sites are the most commonly formed DNA lesions in the cell and are produced by numerous endogenous and environmental insults. In addition, they are generated by the initial step of base excision repair (BER). When located within a topoisomerase II DNA cleavage site, "intact" abasic sites act as topoisomerase II poisons and dramatically stimulate enzyme-mediated DNA scission. However, most abasic sites in cells are not intact. They exist as processed BER intermediates that contain DNA strand breaks proximal to the damaged residue. When strand breaks are located within a topoisomerase II DNA cleavage site, they create suicide substrates that are not religated readily by the enzyme and can generate permanent double-stranded DNA breaks. Consequently, the effects of processed abasic sites on DNA cleavage by human topoisomerase II␣ were examined. Unlike substrates with intact abasic sites, model BER intermediates containing 5-or 3-nicked abasic sites or deoxyribosephosphate flaps were suicide substrates. Furthermore, abasic sites flanked by 5-or 3-nicks were potent topoisomerase II poisons, enhancing DNA scission ϳ10-fold compared with corresponding nicked oligonucleotides that lacked abasic sites. These findings suggest that topoisomerase II is able to convert processed BER intermediates to permanent doublestranded DNA breaks.Topoisomerase II is an indispensable enzyme that regulates nucleic acid topology in vivo by passing an intact doublestranded DNA helix through a second segment of DNA. To create the DNA gate that allows this essential strand passage reaction to occur, the enzyme generates a transient doublestranded break in the second DNA segment (1-4).To maintain the integrity of the genome during the strand passage event, topoisomerase II forms covalent bonds with the

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“…The enzyme then catalyzes a second transesterification in which the free hydroxyl at the 5Ј-end of the nicked DNA strand attacks the phosphotyrosine bond, resealing the nick, and releasing a more relaxed DNA molecule. Topoisomerase I plays a vital role in maintaining DNA stability and is known to travel with active replication and transcription complexes in human cells (4,5).Human topoisomerase I is the sole target of the camptothecins (CPT), a potent class of anticancer drugs used to treat late-term solid malignancies (3,4,6). Camptothecin effectively targets the religation phase of topoisomerase I catalysis by stabilizing the covalent protein-DNA complex and trapping the enzyme on DNA (7,8).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Structural Impact of the Leukemia Drug 1-ॆ-d-Arabinofuranosylcytosine (Ara-C) on the Covalent Human Topoisomerase I-DNA Complex

Chrencik

Burgin²,

Pommier

et al. 2003

Journal of Biological Chemistry

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1-␤-D-Arabinofuranosylcytosine (Ara-C) is a potent antineoplastic drug used in the treatment of acute leukemia. Previous biochemical studies indicated the incorporation of Ara-C into DNA reduced the catalytic activity of human topoisomerase I by decreasing the rate of single DNA strand religation by the enzyme by 2-3-fold. We present the 3.1 Å crystal structure of human topoisomerase I in covalent complex with an oligonucleotide containing Ara-C at the ؉1 position of the non-scissile DNA strand. The structure reveals that a hydrogen bond formed between the 2-hydroxyl of Ara-C and the O4 of the adjacent ؊1 base 5 to the damage site stabilizes a C3-endo pucker in the Ara-C arabinose ring. The structural distortions at the site of damage are translated across the DNA double helix to the active site of human topoisomerase I. The free sulfhydryl at the 5-end of the nicked DNA strand in this trapped covalent complex is shifted out of alignment with the 3-phosphotyrosine linkage at the catalytic tyrosine 723 residue, producing a geometry not optimal for religation. The subtle structural changes caused by the presence of Ara-C in the DNA duplex may contribute to the cytotoxicity of this leukemia drug by prolonging the lifetime of the covalent human topoisomerase I-DNA complex.Human topoisomerase I solves the DNA topological problems that arise from a wide variety of nuclear processes including replication, transcription, and recombination (1, 2). The enzyme nicks one strand of duplex DNA using a transesterification reaction that produces a transient 3Ј-phosphotyrosine linkage and guides the relaxation of either positive or negative superhelical tension by a proposed "controlled rotation" mechanism (3). The enzyme then catalyzes a second transesterification in which the free hydroxyl at the 5Ј-end of the nicked DNA strand attacks the phosphotyrosine bond, resealing the nick, and releasing a more relaxed DNA molecule. Topoisomerase I plays a vital role in maintaining DNA stability and is known to travel with active replication and transcription complexes in human cells (4,5).Human topoisomerase I is the sole target of the camptothecins (CPT), a potent class of anticancer drugs used to treat late-term solid malignancies (3,4,6). Camptothecin effectively targets the religation phase of topoisomerase I catalysis by stabilizing the covalent protein-DNA complex and trapping the enzyme on DNA (7,8). In this way, CPT converts topoisomerase I into a cellular poison. Human topoisomerase I is also affected by several forms of DNA damage, including abasic lesions, wobble base pairs, and base pair mismatches (9 -13). Such lesions can impact each stage of topoisomerase I's catalytic cycle, including DNA binding, single-strand DNA cleavage, and religation.

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DNA Topoisomerases as Anticancer Drug Targets: From the Laboratory to the Clinic

Cited by 102 publications

References 0 publications

Recent Advances in Lamellarin Alkaloids: Isolation, Synthesis and Activity

Recent Advances in Lamellarin Alkaloids: Isolation, Synthesis and Activity

Base Excision Repair Intermediates as Topoisomerase II Poisons

Structural Impact of the Leukemia Drug 1-ॆ-d-Arabinofuranosylcytosine (Ara-C) on the Covalent Human Topoisomerase I-DNA Complex

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