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.
Department of Chemical Theory of Drugs, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia.
Natalia
N
Miklášová
Eva
E
Fischer-Fodor
Peter
P
Lönnecke
Ciprian Ionuţ
CI
Tomuleasa
Piroska
P
Virag
Maria Perde
MP
Schrepler
Roman
R
Mikláš
Luminiţa Silaghi
LS
Dumitrescu
Evamarie
E
Hey-Hawkins
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001152:Arsenicals / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018360:Crystallography, X-Ray; D004249:DNA Damage / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008958:Models, Molecular; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D010165:Palladium / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001152:Arsenicals; D009944:Organoplatinum Compounds; D010165:Palladium