Gallium phosphinoarylbisthiolato complexes counteract drug resistance of cancer cells.

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.

Antiproliferative effect of novel platinum(II) and palladium(II) complexes on hepatic tumor stem cells in vitro.

Novel platinum and palladium complexes with (2-isopropoxyphenyl)dicyclohexylarsine and (2-methoxyphenyl)dicyclohexylarsine ligands were synthesized and tested on different tumor cells. Adducts with general formula MX(2)L(2) (M = Pt(II), Pd(II); X = Cl or I; L = organoarsenic ligand) were fully characterized. According to the crystallographic data, in all complexes the organoarsenic ligands coordinate the metal center through the arsenic atom only, in a trans arrangement with the halogen atoms. The antiproliferative potential of complexes 1-4 was evaluated in vitro on human tumor cell lines. A markedly biological activity was observed against the chemoresistant hepatic tumor stem cell line, the normal hepatic stem cells and towards the hepatocellular carcinoma (non-stem) cells. The new compounds toxicity is selectively limited in normal liver cells, unlikeness with the oxaliplatin, which displays a more intense effect in normal cells, compared with the two tumor cell lines. The stem cells treatment with compounds 1-4 causes DNA damages; the antimitotic effect of these compounds is based on their genotoxicity and on the capacity to form crosslinks with the DNA interstrand. In the case of platinum complexes 1 and 3 this mechanism gives rise to specific lesions on DNA that induces apoptosis in stem cells, influencing their selectivity in tumor cell growth inhibition. Compounds 1, 2 and 4 display higher activity against tumor stem cells. The novel platinum complexes 1 and 3 are more efficient against tumor stem cells than oxaliplatin, and if used in combination with sorafenib-based monoclonal anticancer therapy, complexes 1, 3 and 4 have the ability to induce superior chemosensitivity relative to sorafenib than the standard platinum-based drug, making them promising candidates for prodrug development.

Antiproliferative effect and genotoxicity of novel synthesized palladium complexes with organoarsenic ligands.

Three new palladium complexes with general formula [PdCl(2)L(2)], where L=heterofunctional organoarsenic ligand: (2-isopropoxyphenyl)diphenylarsine (1), (2-methoxyphenyl)-diphenylarsine (2) and (2-hydroxyphenyl)diphenylarsine (3) have been synthesized and fully characterized, including X-ray crystallographic data. Their potential antitumor effect and genotoxicity have been studied as well. The viability test performed on human tumor (MLS) and normal (Hfl-1) cell lines indicates significant cytotoxicity of complexes, which is higher in tumor cells than in normal cells. The lethal doses are comparable with those of standard metal-based chemotherapeutical drugs (carboplatin and oxaliplatin). These palladium complexes exhibit a higher cytotoxicity against tumor cells as against normal cells in vitro. A new static cytometric method was developed and simultaneously the classic AnnexinV test was performed. Complex 2 has an important capacity to induce apoptosis in tumor cells. The apoptotic process is triggered due to the interaction of these complexes with secondary structure of DNA in treated cells. The alkaline single-cell gel assay shows that the level of DNA damages induced by compounds 2 and 3 are significantly higher in tumor cells as in normal cells. These studies shown that complexes 1, 2 and 3 have biologic activity, the effect of complex 2 being superior to its platinum analogues, attributable to its structure.