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: Eva Fischer-Fodor, Ana-Maria Vălean, Piroska Virag, Petru Ilea, Corina Tatomir, Florica Imre-Lucaci, Maria Perde Schrepler, Ludovic Tibor Krausz, Lucian Barbu Tudoran, Calin George Precup, Iulia Lupan, Evamarie Hey-Hawkins, Luminita Silaghi-Dumitrescu
• Journal: Metallomics : integrated biometal science (Metallomics) Vol. 6 Issue 4 Pg. 833-44 (Apr 2014) ISSN: 1756-591X [Electronic] England
• PMID: 24413432 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP-Binding Cassette Transporters
• Antineoplastic Agents
• Coordination Complexes
• Gallium

Topics

• ATP-Binding Cassette Transporters (metabolism)
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Coordination Complexes (chemistry, pharmacology)
• DNA Damage (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Gallium (chemistry, pharmacology)
• Humans
• Models, Molecular
• Neoplasms (drug therapy, genetics, metabolism)