title: Gallium phosphinoarylbisthiolato complexes counteract drug resistance of cancer cells.
abstract: In cancer therapy the platinum-based drugs are used frequently with a good clinical outcome, but besides unwanted side effects which occur, the tumour cells subjected to treatment are prone to develop tolerance or even multidrug resistance (MDR). Metal compounds with a central atom other than platinum are efficient in targeting the chemoresistant cells, therefore the biological outcome of two recently synthesized gallium phosphinoarylbisthiolato complexes was studied, having the formula [X][Ga{PPh(2-SC6H4)2-κ(3)S,S',P}{PPh(2-SC6H4)2-κ(2)S,S'}] where [X] is either the NEt3H (1) or PPh4 (2) cation. Compounds 1 and 2 display in vitro cytotoxicity against both platinum-sensitive and platinum-resistant cell lines (A2780 and A2780cis). Morphological and ultrastructural evidence points toward their capacity to impair tumour cells survival. This behaviour is based on malignant cells capacity to selectively intake gallium, and to bind to the cellular DNA. They are able to cause massive DNA damage in treated cancer cells, focusing on 7-methylguanine and 8-oxoguanine sites and oxidizing the pyrimidine bases; this leads to early apoptosis of a significant percent of treated cells. The intrinsic and extrinsic apoptotic pathways are influenced through the modulation of gene expression following the treatment with complexes 1 and 2, which accompanies the negative regulation of P-glycoprotein 1 (Pgp-1), an important cellular ABC-type transporter from the multidrug resistance (MDR) family. The studied Ga(III) compounds demonstrated the capacity to counteract the chemoresistance mechanisms in the tumours defiant to standard drug action. Compound 2 shows a good anticancer potential and it could represent an alternative to platinum-based drugs especially in the situation of standard treatment failure.
authors.affiliation: Research Department, Oncology Institute "Prof. Dr. I. Chiricuta", 34-36 Republicii Street, Cluj Napoca, RO-400015, Romania. fischer.eva@iocn.ro.
authors.forename: Eva
authors.initials: E
authors.lastname: Fischer-Fodor
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Vălean
authors.forename: Piroska
authors.initials: P
authors.lastname: Virag
authors.forename: Petru
authors.initials: P
authors.lastname: Ilea
authors.forename: Corina
authors.initials: C
authors.lastname: Tatomir
authors.forename: Florica
authors.initials: F
authors.lastname: Imre-Lucaci
authors.forename: Maria Perde
authors.initials: MP
authors.lastname: Schrepler
authors.forename: Ludovic Tibor
authors.initials: LT
authors.lastname: Krausz
authors.forename: Lucian Barbu
authors.initials: LB
authors.lastname: Tudoran
authors.forename: Calin George
authors.initials: CG
authors.lastname: Precup
authors.forename: Iulia
authors.initials: I
authors.lastname: Lupan
authors.forename: Evamarie
authors.initials: E
authors.lastname: Hey-Hawkins
authors.forename: Luminita
authors.initials: L
authors.lastname: Silaghi-Dumitrescu
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005708:Gallium / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D056831:Coordination Complexes; D005708:Gallium