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Enantiopure titanocene complexes: direct evidence for paraptosis in cancer cells

Cini, Melchior; Williams, Huw Edward Llewelyn; Fay, Mike W.; Searle, Mark; Woodward, Simon; Bradshaw, Tracey D.

Authors

Melchior Cini

Huw Edward Llewelyn Williams

Mark Searle

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SIMON WOODWARD simon.woodward@nottingham.ac.uk
Professor of Synthetic Organic Chemistry

Tracey D. Bradshaw



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{n-C5H4CHEt(2 MeOPh)}2 (abbreviated CpR 2TiCl2) has been investigated. The in vitro anti-tumour activity of CpR 2TiCl2 is selective for cancer cells; in clonogenic assays, (S,S)-CpR 2TiCl2 was twice as effective at inhibiting colony formation than other stereoisomers after 24 h exposure. HPLC, MS and NMR techniques determined hydrolysis of CpR 2TiCl2; data strongly correlate with soluble [CpR 2Ti(OH (OH2)]+ being the biological trigger. Treatment of cells with CpR 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, CpR 2TiCl2 failed to perturb cell cycle dynamics, induce ?H2AX foci or evoke apoptosis in MDA-MB-468 and HCT-116 cells.

Citation

Cini, M., Williams, H. E. L., Fay, M. W., Searle, M., Woodward, S., & Bradshaw, T. D. (2016). Enantiopure titanocene complexes: direct evidence for paraptosis in cancer cells. Metallomics, https://doi.org/10.1039/C5MT00297D

Journal Article Type Article
Publication Date Jan 18, 2016
Deposit Date Jan 26, 2016
Publicly Available Date Mar 29, 2024
Journal Metallomics
Print ISSN 1756-5901
Electronic ISSN 1756-591X
Publisher Royal Society of Chemistry
Peer Reviewed Peer Reviewed
DOI https://doi.org/10.1039/C5MT00297D
Keywords Titanocenes, chiral cyclopentadienyls, paraptosis, cancer
Public URL https://nottingham-repository.worktribe.com/output/772411
Publisher URL http://pubs.rsc.org/en/Content/ArticleLanding/2016/MT/C5MT00297D#!divAbstract

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