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Inhibition of topoisomerase II? and induction of DNA damage in cholangiocarcinoma cells by altholactone and its halogenated benzoate derivatives - 30/05/20

Doi : 10.1016/j.biopha.2020.110149 
Sarunya Kitdumrongthum a, b, Somrudee Reabroi c, Kanoknetr Suksen d, Patoomratana Tuchinda b, e, Bamroong Munyoo b, e, Panupong Mahalapbutr f, Thanyada Rungrotmongkol f, g, Puey Ounjai h, Arthit Chairoungdua a, b, d,
a Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand 
b Excellent Center for Drug Discovery (ECDD), Mahidol University, Bangkok, Thailand 
c Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand 
d Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand 
e Department of Chemistry, Faculty of Science, Mahidol University, Bangkok, Thailand 
f Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand 
g Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, Thailand 
h Department of Biology, Faculty of Science, Mahidol University, Bangkok, Thailand 

Corresponding author at: Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Rd., Ratchathewi, Bangkok 10400, Thailand.Department of PhysiologyFaculty of ScienceMahidol UniversityRama 6 Rd.RatchathewiBangkok10400Thailand

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Highlights

Halogenated benzoate derivatives inhibited Topo IIα activity.
Halogenated benzoate derivatives was more potent than altholactone.
Fluorobenzoate derivative and altholactone binds to ATPase domain of Topo II.
Fluorobenzoate derivative suppressed Topo IIα protein expression.
Fluorobenzoate derivative induced DSBs in CCA cells and caused apoptosis.

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Abstract

Topoisomerase IIα enzyme (Topo IIα) plays a critical function in DNA replication process and is considered to be a promising target of anti-cancer drugs. In the present study, we reported that the altholactone derivatives modified by adding a halogenated benzoate group showed greater inhibitory activity on Topo IIα enzyme in cell-free system concomitant with cytotoxicity against the CCA cell lines (KKU-M055 and KKU-M213) than those of the parent altholactone. However, the cytotoxic activities of four halogenated benzoate altholactone derivatives including iodo-, fluoro-, chloro-, and bromobenzoate derivatives (compound 1, 2, 3, and 4, respectively) were of equal potency. The fluorobenzoate derivative (compound 2) was chosen for investigating the underlying mechanism in CCA cells. Compound 2 arrested CCA cell cycle at sub G1 phase and induced apoptotic cell death. It markedly inhibited Topo IIα protein expression in both KKU-M055 and KKU-M213 cells, which was accompanied by DNA double-strand breaks demonstrated by an increase in phosphorylated H2A.X protein. Interestingly, KKU-M055 cells, which express higher Topo IIα mRNA compared to KKU-M213 cells, showed greater sensitivity to the compound, indicating the selectivity of the compound to Topo IIα enzyme. By computational docking analysis, the binding affinity of altholactone (-52.5 kcal/mol) and compound 2 (-56.7 kcal/mol) were similar to that of the Topo II poison salvicine (-53.7 kcal/mol). The aromatic moiety of both altholactones embedded in a hydrophobic pocket of Topo II ATPase domain. In addition, compound 2 induced the formation of linear DNA in Topo II-mediated cleavage assay. Collectively, our results demonstrate that the addition of fluorobenzoyl group to altholactone enhances potency and selectivity to inhibit type IIα topoisomerases. Atholactone and fluorobenzoate derivative act as Topo II cleavage complexes stabilizing compounds or Topo II poisons preferentially through binding at ATPase domain of Topo IIα, leading to DNA double-strand breaks and apoptosis induction. Such activity of 3-fluorobenzoate derivative of altholactone should be further explored for the development of an anti-cancer drug for CCA.

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Keywords : Altholactone, Halogenated benzoate, Cholangiocarcinoma, Topoisomerase IIα


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