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 MX2L2 (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.

New platinum/palladium complexes (1–4) with tertiary arsenic ligands were biologically tested in vitro on tumor hepatic stem cells (CSC), non-tumor hepatic cells and HepG2 non-stem liver cells. Complexes 1–4 are selective towards tumor cells, and their genotoxicity against hepatic cells causes irreparable DNA lesions.Figure optionsDownload as PowerPoint slideHighlights
► Novel platinum(II) and palladium(II) complexes with organoarsenic ligands, with antiproliferative potential.
► In vitro anti-tumor activity against human chemoresistant hepatic stem-like stems cells and non-stem tumoral cell lines.
► New complexes genotoxicity, the capacity to form crosslinks with the DNA and to induce apoptosis in stem cells.