Structural and Metal Ion Effects on Human Topoisomerase IIα Inhibition by α-(N)-Heterocyclic Thiosemicarbazones

Morris, William; Ngo, Lana; Wilson, James T.; Medawala, Wathsala; Brown, Anthony R.; Conner, Jennifer D.; Fabunmi, Florence; Cashman, Derek J.; Lisic, Edward C.; Yu, Tao; Deweese, Joseph E.; Jiang, Xianzhen

doi:10.1021/acs.chemrestox.8b00204

Cited by 16 publications

(31 citation statements)

References 38 publications

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“…Piperazine-TSCs based CuC 16 inhibit Top2α [ 101 , 102 ] by a strong interaction with the ATP-binding pocket residues [ 99 ] without ROS production [ 102 ]. Thiazole-TSC CuC 17 and 18 are Top2α catalytic inhibitors [ 103 , 104 ] or poisons [ 105 ]. The highly water-soluble proline-TSC CuC series 19 inhibit Top2α and cell proliferation [ 106 ].…”

Section: Copper Complexes As Topoisomerases Inhibitorsmentioning

confidence: 99%

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

Molinaro

Martoriati

Pélinski

et al. 2020

Cancers

119

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Organometallics, such as copper compounds, are cancer chemotherapeutics used alone or in combination with other drugs. One small group of copper complexes exerts an effective inhibitory action on topoisomerases, which participate in the regulation of DNA topology. Copper complexes inhibitors of topoisomerases 1 and 2 work by different molecular mechanisms, analyzed herein. They allow genesis of DNA breaks after the formation of a ternary complex, or act in a catalytic mode, often display DNA intercalative properties and ROS production, and sometimes display dual effects. These amplified actions have repercussions on the cell cycle checkpoints and death effectors. Copper complexes of topoisomerase inhibitors are analyzed in a broader synthetic view and in the context of cancer cell mutations. Finally, new emerging treatment aspects are depicted to encourage the expansion of this family of highly active anticancer drugs and to expend their use in clinical trials and future cancer therapy.

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Section: Copper Complexes As Topoisomerases Inhibitorsmentioning

confidence: 99%

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

Molinaro

Martoriati

Pélinski

et al. 2020

Cancers

119

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“…14 Other α-(N)-heterocyclic thiosemicarbazones have been synthesized and chelated to different divalent metal ions that display unique activity signatures against TOP2. 6,7,11,16 Copper(II) [Cu(II)] thiosemicarbazone complexes generally display high levels of activity against TOP2. 6,16,17 Not only do these Cu(II) thiosemicarbazone complexes act against TOP2, but previous studies from our group and others have shown that some of the same compounds are active against cancer cell lines at nanomolar to micromolar concentrations.…”

Section: ■ Introductionmentioning

confidence: 99%

“…6,7,11,16 Copper(II) [Cu(II)] thiosemicarbazone complexes generally display high levels of activity against TOP2. 6,16,17 Not only do these Cu(II) thiosemicarbazone complexes act against TOP2, but previous studies from our group and others have shown that some of the same compounds are active against cancer cell lines at nanomolar to micromolar concentrations. 7,9−11 Humans have two isoforms of topoisomerase II, IIα and IIβ.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Previous studies have demonstrated that Cu(II) metal complexes of α-(N)-heterocyclic thiosemicarbazones demonstrate higher levels of activity against TOP2 versus other metal complexes. 6,11,16,17 Therefore, we tested Cu(II) metal complexes against human TOP2A. Evidence from our studies suggests that these compounds act as catalytic inhibitors but can also induce high levels of DNA cleavage.…”

Section: ■ Introductionmentioning

confidence: 99%

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Clarifying the Mechanism of Copper(II) α-(N)-Heterocyclic Thiosemicarbazone Complexes on DNA Topoisomerase IIα and IIβ

Keck

Conner

Wilson

et al. 2019

Chem. Res. Toxicol.

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During replication, transcription, and cell division, knots and tangles can form in DNA. To relieve this stress, type II topoisomerases are employed, which use a transient enzyme‐linked double strand break to remove the knots and tangles formed within the DNA. Furthermore, because the cell has an immediate need for topoisomerase II activity in order to properly perform cellular functions, topoisomerase II has become a target of interest for anticancer therapy. Over the past several years, a class of compounds termed α‐(N)‐heterocyclic thiosemicarbazones have been identified as a possible anticancer therapy option due to their ability to impact topoisomerase II activity. Moreover, literature evidence suggests that copper complexes [Cu(II)] of α‐(N)‐heterocyclic thiosemicarbazones act as catalytic inhibitors of topoisomerase II similar to the topoisomerase II inhibitor Dexrazoxane. Previously, our lab demonstrated activity against human topoisomerase IIα, but there is a second isoform in humans, topoisomerase IIβ, which has been largely unexplored with thiosemicarbazones. Therefore, we set out to determine the mechanism of two Cu(II) complexes of α‐(N)‐heterocyclic thiosemicarbazones as inhibitors of topoisomerase IIβ. The Cu(II) complexes, copper(II) acetylpyridine‐ethylthiosemicarbazone [Cu(APY‐ETSC)Cl] and copper(II)benzoylpyridine‐ethylthiosemicarbazone [Cu(BZP‐ETSC)Cl] were examined for their ability to alter the catalytic activity of topoisomerase IIβ. Both Cu(II) complexes were effective at inhibiting DNA relaxation at around 10–25 μM. Additionally, both Cu(II) complexes increased double‐stranded DNA cleavage peaking around 25–50 μM. When narrowing the focus to just Cu(APY‐ETSC)Cl and Cu(BZP‐ETSC)Cl, it was determined that both compounds interfere with ATP hydrolysis of topoisomerase IIβ, which is required for strand passage. Additional experiments determined that ATP cannot outcompete Cu(APY‐ETSC)Cl or Cu(BZP‐ETSC)Cl for binding to topoisomerase IIβ, which suggests that these compounds bind outside the ATP binding pocket but allosterically impact ATP hydrolysis. Lastly, we examined whether the Cu(II) complexes could stabilize the N‐terminal ATPase domain in a closed conformation similar to ATP. Both compounds stabilize the N‐terminal closed conformation of the ATPase domain, suggesting a mechanism for topoisomerase II inhibition by these compounds. Taken together, these results provide evidence that Cu(II) complexes of α‐(N)‐heterocyclic thiosemicarbazones catalytically inhibit topoisomerase IIβ similar to topoisomerase IIα. Additionally, the mechanism involves binding to the ATPase domain outside of the ATP pocket and inducing a closed N‐terminal gate of topoisomerase II. These results also provide a possible explanation for the increase in topoisomerase II‐mediated DNA cleavage observed in the presence of Cu(II) thiosemicarbazone complexes. Support or Funding Information JMK and JED were supported by LUCOPHS. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associ...

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“…To date, all clinical TopoII poisons are nonspecific with regard to TopoIIα and TopoIIβ and affect the DNA cleavage activity of both isoforms. ,,− However, the contribution of each isoform to the therapeutic effects of drugs is not well understood. ,− In this regard, both cellular and in vivo studies suggest that TopoIIβ is primarily responsible for generating the breaks in the mixed lineage leukemia ( MLL ) gene that initiate the acute myelogenous leukemias that are associated with etoposide treatment. ,, Strong support for this hypothesis comes from studies with a skin carcinogenesis model, where the incidence of secondary malignancies was curtailed in a TopoIIβ-knockout mouse . Further, TopoIIβ was also related to etoposide-induced DNA sequence rearrangements and double-strand breaks in a murine cell model .…”

Section: Introductionmentioning

confidence: 99%

Smoothed Potential MD Simulations for Dissociation Kinetics of Etoposide To Unravel Isoform Specificity in Targeting Human Topoisomerase II

Kuriappan

Osheroff

Vivo

2019

J. Chem. Inf. Model.

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Human type II topoisomerases (TopoII) are essential for controlling DNA topology within the cell. For this reason, there are a number of TopoII-targeted anticancer drugs that act by inducing DNA cleavage mediated by both TopoII isoforms (TopoIIα and TopoIIβ) in cells. However, recent studies suggest that specific poisoning of TopoIIα may be a safer strategy for treating cancer. This is because poisoning of TopoIIβ appears to be linked to the generation of secondary leukemia in patients. We recently reported that enzyme-mediated DNA cleavage complexes (in which TopoII is covalently linked to the cleaved DNA during catalysis) formed in the presence of the anticancer drug etoposide persisted approximately 3-fold longer with TopoIIα than TopoIIβ. Notably, enhanced drug-target residence time may reduce the adverse effects of specific TopoIIα poisons. However, it is still not clear how to design drugs that are specific for the α isoform. In this study, we report the results of classical molecular dynamics (MD) simulations to comparatively analyze the molecular interactions formed within the TopoII/DNA/etoposide complex with both isoforms. We also used smoothed potential MD to estimate etoposide dissociation kinetics from the two isoform complexes. These extensive classical and enhanced sampling simulations revealed stabilizing interactions of etoposide with two serine residues (Ser763 and Ser800) in TopoIIα. These interactions are missing in TopoIIβ, where both amino acids are alanine residues. This may explain the greater persistence of etoposide-stabilized cleavage complexes formed with Topo TopoIIα. These findings could be useful for the rational design of specific TopoIIα poisons.

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Structural and Metal Ion Effects on Human Topoisomerase IIα Inhibition by α-(N)-Heterocyclic Thiosemicarbazones

Cited by 16 publications

References 38 publications

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

Clarifying the Mechanism of Copper(II) α-(N)-Heterocyclic Thiosemicarbazone Complexes on DNA Topoisomerase IIα and IIβ

Smoothed Potential MD Simulations for Dissociation Kinetics of Etoposide To Unravel Isoform Specificity in Targeting Human Topoisomerase II

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