title: Isoeugenol is a selective potentiator of camptothecin cytotoxicity in vertebrate cells lacking TDP1.
abstract: Camptothecin (CPT), a topoisomerase I (TOP1) inhibitor, exhibits anti-tumor activity against a wide range of tumors. Redundancy of TOP1-mediated repair mechanisms is a major challenge facing the efficiency of TOP1-targetting therapies. This study aims to uncover new TOP1 targeting approaches utilising a selection of natural compounds in the presence or absence of tyrosyl DNA phosphodiesterase I (TDP1); a key TOP1-mediated protein-linked DNA break (PDB) repair enzyme. We identify, isoeugenol, a phenolic ether found in plant essential oils, as a potentiator of CPT cytotoxicity in Tdp1 deficient but not proficient cells. Consistent with our cellular data, isoeugenol did not inhibit Tdp1 enzymatic activity in vitro nor it sensitized cells to the PARP1 inhibitor olaparib. However, biochemical analyses suggest that isoeugenol inhibits TDP2 catalytic activity; a pathway that can compensate for the absence of TDP1. Consistent with this, isoeugenol exacerbated etoposide-induced cytotoxicity, which generates TOP2-mediated PDBs for which TDP2 is required for processing. Together, these findings identify isoeugenol as a potential lead compound for developing TDP2 inhibitors and encourage structure-activity relationship studies to shed more light on its utility in drug discovery programs.
authors.affiliation: Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza, Egypt.
authors.forename: Waheba
authors.initials: W
authors.lastname: Elsayed
authors.affiliation: Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza, Egypt.
authors.forename: Lamia
authors.initials: L
authors.lastname: El-Shafie
authors.affiliation: Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza, Egypt.|Biotechnology Dept., Faculty of Science, Port Said University, Egypt.
authors.forename: Mohamed K
authors.initials: MK
authors.lastname: Hassan
authors.affiliation: Department of Pharamcognosy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Farag
authors.affiliation: Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza, Egypt.|Krebs Institute, University of Sheffield, Sheffield, S10 2TN, UK.
authors.forename: Sherif F
authors.initials: SF
authors.lastname: El-Khamisy
mesh_terms: D002166:Camptothecin / Q000819:agonists / Q000494:pharmacology*; D002460:Cell Line; D003603:Cytotoxins / Q000819:agonists / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D005054:Eugenol / Q000819:agonists / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000172:deficiency*; D000075223:Poly-ADP-Ribose Binding Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D003603:Cytotoxins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D014157:Transcription Factors; D005054:Eugenol; C036643:isoeugenol; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human; C474866:TDP2 protein, human; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; D002166:Camptothecin