TY - JOUR
T1 - An Organometallic Gold(I) Bis-N-Heterocyclic Carbene Complex with Multimodal Activity in Ovarian Cancer Cells
AU - Meier-Menches, Samuel M.
AU - Neuditschko, Benjamin
AU - Zappe, Katja
AU - Schaier, Martin
AU - Gerner, Marlene C.
AU - Schmetterer, Klaus G.
AU - Del Favero, Giorgia
AU - Bonsignore, Riccardo
AU - Cichna-Markl, Margit
AU - Koellensperger, Gunda
AU - Casini, Angela
AU - Gerner, Christopher
N1 - © 2020 The Authors. Published by Wiley-VCH GmbH.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - The organometallic AuI bis-N-heterocyclic carbene complex [Au(9-methylcaffeine-8-ylidene)2]+ (AuTMX2) was previously shown to selectively and potently stabilise telomeric DNA G-quadruplex (G4) structures. This study sheds light on the molecular reactivity and mode of action of AuTMX2 in the cellular context using mass spectrometry-based methods, including shotgun proteomics in A2780 ovarian cancer cells. In contrast to other metal-based anticancer agents, this organogold compound is less prone to form coordinative bonds with biological nucleophiles and is expected to exert its drug effects mainly by non-covalent interactions. Global protein expression changes of treated cancer cells revealed a multimodal mode of action of AuTMX2 by alterations in the nucleolus, telomeres, actin stress-fibres and stress-responses, which were further supported by pharmacological assays, fluorescence microscopy and cellular accumulation experiments. Proteomic data are available via ProteomeXchange with identifier PXD020560.
AB - The organometallic AuI bis-N-heterocyclic carbene complex [Au(9-methylcaffeine-8-ylidene)2]+ (AuTMX2) was previously shown to selectively and potently stabilise telomeric DNA G-quadruplex (G4) structures. This study sheds light on the molecular reactivity and mode of action of AuTMX2 in the cellular context using mass spectrometry-based methods, including shotgun proteomics in A2780 ovarian cancer cells. In contrast to other metal-based anticancer agents, this organogold compound is less prone to form coordinative bonds with biological nucleophiles and is expected to exert its drug effects mainly by non-covalent interactions. Global protein expression changes of treated cancer cells revealed a multimodal mode of action of AuTMX2 by alterations in the nucleolus, telomeres, actin stress-fibres and stress-responses, which were further supported by pharmacological assays, fluorescence microscopy and cellular accumulation experiments. Proteomic data are available via ProteomeXchange with identifier PXD020560.
KW - cancer
KW - G-quadruplexes
KW - gold complexes
KW - N-heterocyclic carbenes
KW - proteomics
KW - telomeres
KW - Humans
KW - Methane/analogs & derivatives
KW - Gold/chemistry
KW - Antineoplastic Agents/pharmacology
KW - Ovarian Neoplasms/drug therapy
KW - Proteomics
KW - Cell Line, Tumor
KW - Female
KW - Caffeine/analogs & derivatives
KW - Organometallic Compounds/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85096654701&partnerID=8YFLogxK
U2 - 10.1002/chem.202003495
DO - 10.1002/chem.202003495
M3 - Article
C2 - 32902006
AN - SCOPUS:85096654701
SN - 0947-6539
VL - 26
SP - 15528
EP - 15537
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
IS - 67
ER -
