title: Enantiopure titanocene complexes--direct evidence for paraptosis in cancer cells.
abstract: Tolerated by normal tissues, anti-cancer therapies based on titanium compounds are limited by low efficacy/selectivity and lack of understanding of their mode(s) of action. In vitro antitumour activity and mode of cell death incurred by enantiopure TiCl2{η-C5H4CHEt(2-MeOPh)}2 (abbreviated Cp(R)2TiCl2) has been investigated. The in vitro anti-tumour activity of Cp(R)2TiCl2 is selective for cancer cells; in clonogenic assays, (S,S)-Cp(R)2TiCl2 was twice as effective at inhibiting colony formation than other stereoisomers after 24 h exposure. HPLC, MS and NMR techniques determined hydrolysis of Cp(R)2TiCl2; data strongly correlate with soluble [Cp(R)2Ti(OH)(OH2)](+) being the biological trigger. Treatment of cells with Cp(R)2TiCl2 provoked extensive cytoplasmic vacuolization, endoplasmic reticulum (ER) swelling and activation of MAPKinase signal transduction, consistent with ligand-induced paraptosis, type III cell death, which is morphologically distinct from, and independent of apoptosis. Indeed, distinct from cisplatin, Cp(R)2TiCl2 failed to perturb cell cycle dynamics, induce γH2AX foci or evoke apoptosis in MDA-MB-468 and HCT-116 cells.
authors.affiliation: School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK. simon.woodward@nottingham.ac.uk cinimelchior@gmail.com and School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK. tracey.bradshaw@nottingham.ac.uk and Nottingham Nanotechnology and Nanoscience Centre, University of Nottingham, University Park, Nottingham NG7 2RD, UK and Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
authors.forename: Melchior
authors.initials: M
authors.lastname: Cini
authors.affiliation: School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK. simon.woodward@nottingham.ac.uk cinimelchior@gmail.com and Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
authors.forename: Huw
authors.initials: H
authors.lastname: Williams
authors.affiliation: Nottingham Nanotechnology and Nanoscience Centre, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
authors.forename: Mike W
authors.initials: MW
authors.lastname: Fay
authors.affiliation: School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK. simon.woodward@nottingham.ac.uk cinimelchior@gmail.com and Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Searle
authors.affiliation: School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK. simon.woodward@nottingham.ac.uk cinimelchior@gmail.com.
authors.forename: Simon
authors.initials: S
authors.lastname: Woodward
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK. tracey.bradshaw@nottingham.ac.uk and Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
authors.forename: Tracey D
authors.initials: TD
authors.lastname: Bradshaw
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D005434:Flow Cytometry; D006657:Histones / Q000378:metabolism; D006801:Humans; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy; D013237:Stereoisomerism
chemical_list: C468783:H2AX protein, human; D006657:Histones; D009942:Organometallic Compounds; C406884:titanocene; D002945:Cisplatin