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Dual Inhibitors Against Topoisomerases and Histone Deacetylases.

Seo YH - J Cancer Prev (2015)

Bottom Line: Topoisomerases are involved in the cleavage and religation processes of DNA, while HDACs regulate a dynamic epigenetic modification of the lysine amino acid on various proteins.Extensive studies have been undertaken to discover small molecule inhibitor of each protein and thereby, several drugs have been transpired from this effort and successfully approved for clinical use.This review highlights the current studies on the discovery of dual inhibitors against topoisomerases and HDACs, provides their pharmacological aspects and advantages, and discusses the challenges and promise of the dual inhibitors.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Keimyung University, Daegu, Korea.

ABSTRACT
Topoisomerases and histone deacetylases (HDACs) are considered as important therapeutic targets for a wide range of cancers, due to their association with the initiation, proliferation and survival of cancer cells. Topoisomerases are involved in the cleavage and religation processes of DNA, while HDACs regulate a dynamic epigenetic modification of the lysine amino acid on various proteins. Extensive studies have been undertaken to discover small molecule inhibitor of each protein and thereby, several drugs have been transpired from this effort and successfully approved for clinical use. However, the inherent heterogeneity and multiple genetic abnormalities of cancers challenge the clinical application of these single targeted drugs. In order to overcome the limitations of a single target approach, a novel approach, simultaneously targeting topoisomerases and HDACs with a single molecule has been recently employed and attracted much attention of medicinal chemists in drug discovery. This review highlights the current studies on the discovery of dual inhibitors against topoisomerases and HDACs, provides their pharmacological aspects and advantages, and discusses the challenges and promise of the dual inhibitors.

No MeSH data available.


Related in: MedlinePlus

Schematic illustration of topoisomerase I (TopI, left) and II (TopII, right). (A) Noncovalent binding of TopI and (D) TopII to DNA. Under normal conditions, TopI and TopII cleave and religate DNA and religation is a faster process than cleavage, so cleavage complexes are transient intermediates. The arrow indicates the reversible ligation and cleavage reaction under normal condition (A, B for TopI and D, E for TopII). (C) Trapping the cleavage complexes of DNA-topoisomerases by TopI inhibitors and (F) TopII inhibitors promotes DNA damages.
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f1-jcp-20-85: Schematic illustration of topoisomerase I (TopI, left) and II (TopII, right). (A) Noncovalent binding of TopI and (D) TopII to DNA. Under normal conditions, TopI and TopII cleave and religate DNA and religation is a faster process than cleavage, so cleavage complexes are transient intermediates. The arrow indicates the reversible ligation and cleavage reaction under normal condition (A, B for TopI and D, E for TopII). (C) Trapping the cleavage complexes of DNA-topoisomerases by TopI inhibitors and (F) TopII inhibitors promotes DNA damages.

Mentions: In human, the entire genome of a single cell needs to be squeezed into 2- to 10-μm diameter of a tiny nucleus.10 To maintain this DNA compaction, enzymes capable of managing superhelical tension and knots are necessarily required. Topoisomerases, including topoisomerase I and II, are ubiquitous enzymes that control DNA supercoiling and entanglements (Fig. 1).9,10 The opening of double-stranded DNA and separation of these two strands during transcription and replication produce positive (left-handed) and negative (right-handed) supercoiling on either side of open DNA segment. Positive supercoiling and consequent tightening of DNA prevent separation of its two strands, and further impair the polymerization of DNA. Therefore, without topoisomerases, excessive positive supercoiling and entanglements of DNA eventually stall transcription and replication. Topoisomerase I relieves the torsional strain on DNA during DNA replication by cleaving one stand of a DNA double helix and passing one strand over the other, while topoisomerase II removes knots and tangles by generating transient double-stranded breaks in the double helix (Fig. 1).17–20 Cleavage of DNA occurs by transesterification reactions, in which an active tyrosine residue of topoisomerases attacks the phosphodiester linkages of DNA to form tyrosyl-DNA covalent bonds at the end of the break (Fig. 1B and 1E). Topoisomerase I breaks DNA by forming a tyrosyl-DNA covalent bond at the 3’ end of the break, whereas topoisomerase II cuts DNA by covalent attachment to the 5’ end of the break. Under normal conditions, topoisomerases process the cleaving and religating reactions very rapidly, in that the religation reactions occur faster than cleavage reactions, thereby the complexes of topoisomerases-DNA are considered transient. A number of topoisomerase inhibitors have been proven to exhibit anticancer effects by stabilizing the complexes of topoisomerases-DNA through specifically binding at the interface of topoisomerases-DNA complexes (Fig. 1C and 1F). Inhibitors of topoisomerase I stabilize topoisomerase I and DNA cleavage complexes, prevent the religation of DNA, and induce lethal DNA strand breaks. Inhibitors of topoisomerase I are commonly used to treat several cancers including ovarian, lung, breast, colon and cervical cancer. In contrast, inhibitors of topoisomerase II trap topoisomerase II and DNA cleavage complexes, and are used for lymphoma, leukemia, testicular, and lung cancer.


Dual Inhibitors Against Topoisomerases and Histone Deacetylases.

Seo YH - J Cancer Prev (2015)

Schematic illustration of topoisomerase I (TopI, left) and II (TopII, right). (A) Noncovalent binding of TopI and (D) TopII to DNA. Under normal conditions, TopI and TopII cleave and religate DNA and religation is a faster process than cleavage, so cleavage complexes are transient intermediates. The arrow indicates the reversible ligation and cleavage reaction under normal condition (A, B for TopI and D, E for TopII). (C) Trapping the cleavage complexes of DNA-topoisomerases by TopI inhibitors and (F) TopII inhibitors promotes DNA damages.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492363&req=5

f1-jcp-20-85: Schematic illustration of topoisomerase I (TopI, left) and II (TopII, right). (A) Noncovalent binding of TopI and (D) TopII to DNA. Under normal conditions, TopI and TopII cleave and religate DNA and religation is a faster process than cleavage, so cleavage complexes are transient intermediates. The arrow indicates the reversible ligation and cleavage reaction under normal condition (A, B for TopI and D, E for TopII). (C) Trapping the cleavage complexes of DNA-topoisomerases by TopI inhibitors and (F) TopII inhibitors promotes DNA damages.
Mentions: In human, the entire genome of a single cell needs to be squeezed into 2- to 10-μm diameter of a tiny nucleus.10 To maintain this DNA compaction, enzymes capable of managing superhelical tension and knots are necessarily required. Topoisomerases, including topoisomerase I and II, are ubiquitous enzymes that control DNA supercoiling and entanglements (Fig. 1).9,10 The opening of double-stranded DNA and separation of these two strands during transcription and replication produce positive (left-handed) and negative (right-handed) supercoiling on either side of open DNA segment. Positive supercoiling and consequent tightening of DNA prevent separation of its two strands, and further impair the polymerization of DNA. Therefore, without topoisomerases, excessive positive supercoiling and entanglements of DNA eventually stall transcription and replication. Topoisomerase I relieves the torsional strain on DNA during DNA replication by cleaving one stand of a DNA double helix and passing one strand over the other, while topoisomerase II removes knots and tangles by generating transient double-stranded breaks in the double helix (Fig. 1).17–20 Cleavage of DNA occurs by transesterification reactions, in which an active tyrosine residue of topoisomerases attacks the phosphodiester linkages of DNA to form tyrosyl-DNA covalent bonds at the end of the break (Fig. 1B and 1E). Topoisomerase I breaks DNA by forming a tyrosyl-DNA covalent bond at the 3’ end of the break, whereas topoisomerase II cuts DNA by covalent attachment to the 5’ end of the break. Under normal conditions, topoisomerases process the cleaving and religating reactions very rapidly, in that the religation reactions occur faster than cleavage reactions, thereby the complexes of topoisomerases-DNA are considered transient. A number of topoisomerase inhibitors have been proven to exhibit anticancer effects by stabilizing the complexes of topoisomerases-DNA through specifically binding at the interface of topoisomerases-DNA complexes (Fig. 1C and 1F). Inhibitors of topoisomerase I stabilize topoisomerase I and DNA cleavage complexes, prevent the religation of DNA, and induce lethal DNA strand breaks. Inhibitors of topoisomerase I are commonly used to treat several cancers including ovarian, lung, breast, colon and cervical cancer. In contrast, inhibitors of topoisomerase II trap topoisomerase II and DNA cleavage complexes, and are used for lymphoma, leukemia, testicular, and lung cancer.

Bottom Line: Topoisomerases are involved in the cleavage and religation processes of DNA, while HDACs regulate a dynamic epigenetic modification of the lysine amino acid on various proteins.Extensive studies have been undertaken to discover small molecule inhibitor of each protein and thereby, several drugs have been transpired from this effort and successfully approved for clinical use.This review highlights the current studies on the discovery of dual inhibitors against topoisomerases and HDACs, provides their pharmacological aspects and advantages, and discusses the challenges and promise of the dual inhibitors.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Keimyung University, Daegu, Korea.

ABSTRACT
Topoisomerases and histone deacetylases (HDACs) are considered as important therapeutic targets for a wide range of cancers, due to their association with the initiation, proliferation and survival of cancer cells. Topoisomerases are involved in the cleavage and religation processes of DNA, while HDACs regulate a dynamic epigenetic modification of the lysine amino acid on various proteins. Extensive studies have been undertaken to discover small molecule inhibitor of each protein and thereby, several drugs have been transpired from this effort and successfully approved for clinical use. However, the inherent heterogeneity and multiple genetic abnormalities of cancers challenge the clinical application of these single targeted drugs. In order to overcome the limitations of a single target approach, a novel approach, simultaneously targeting topoisomerases and HDACs with a single molecule has been recently employed and attracted much attention of medicinal chemists in drug discovery. This review highlights the current studies on the discovery of dual inhibitors against topoisomerases and HDACs, provides their pharmacological aspects and advantages, and discusses the challenges and promise of the dual inhibitors.

No MeSH data available.


Related in: MedlinePlus