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.

Coordination compounds in cancer: Past, present and perspectives

“…They bind DNA in 7-methylguanine and 8-oxoguanine positions, oxidizing the pyrimidine bases and inducing apoptosis. These complexes show in vitro antitumor activity against the cisplatin-resistant ovarian tumour cell line A2780cis (Fischer-Fodor et al, 2014). Complexes with N,N,O donors have been also tested against ovarian, breast, and prostate adenocarcinoma cell lines.…”

“…The biological action of these complexes is due to the inhibition of proteasome with activation of apoptosis (Chen et al, 2007). Recently, the antitumor activity of phosphinoarylbisthiolato gallium(III) complexes was reported (Fischer-Fodor et al, 2014). They bind DNA in 7-methylguanine and 8-oxoguanine positions, oxidizing the pyrimidine bases and inducing apoptosis.…”

Lipophilicity-dependent ruthenium N-heterocyclic carbene complexes as potential anticancer agents

“…2 To address these drawbacks, exploration of novel metal complexes with better pharmacokinetic and pharmacodynamic properties has been initiated. [3][4][5][6] As is well known, the properties of the ligand play an important role in the bioactivities of the metal complexes. Among these, metal complexes of the N-heterocyclic carbene (NHC) ligand have recently shown very promising results.…”

In vitro Antitumour Activity of Tomato-Extracted Carotenoids on Human Colorectal Carcinoma

“…The cytotoxicity of the compounds was measured in colorimetry using the MTT dye (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, from Sigma Aldrich), following a protocol described before (Fischer-Fodor et al, 2014). In living cells, the MTT is transformed into insoluble formazan as a result of the mitochondrial enzymatic activity; formazan crystals were solubilized in dimethylsulphoxyde (Titolchimica, Italy), and the 96-well plates were measured with a Synergy 2.0 microplate reader (from BioTek Company, Winooski, USA) at 570nm wavelength.…”