Anti-cancer activity and mutagenic potential of novel copper(II) quinolinone Schiff base complexes in hepatocarcinoma cells.
This study determined the cytotoxic, cyto-selective and mutagenic potential of novel quinolinone Schiff base ligands and their corresponding copper(II) complexes in human-derived hepatic carcinoma cells (Hep-G2) and non-malignant human-derived hepatic cells (Chang). Results indicated that complexation of quinolinone Schiff bases with copper served to significantly enhance cytotoxicity. Here, the complex of (7E)-7-(3-ethoxy-2-hydroxybenzylideamino)-4-methylquinolin-2(1H)-one (TV117-FM) exhibited the lowest IC(50) value (17.9 μM) following 96 h continuous exposure, which was comparable to cisplatin (15.0 μM). However, results revealed that TV117-FM lacked cytoselectivity over non-malignant cells. Additionally, the complex was minimally effluxed from cells via Pglycoprotein (P-gp) and was shown to be non-mutagenic in the Standard Ames test. Furthermore, BrdU incorporation assays showed that it was capable of inhibiting DNA synthesis in a concentrationand time-dependent manner. However, inhibition was not as a consequence of DNA intercalation, as illustrated in electrophoretic mobility shift assays. Interestingly, it was shown that the ligand was capable of inhibiting the action of topoisomerase II, but this was lost following complexation. This indicated that the mechanism of action of the novel copper(II) complex was different from that of the parent ligand and suggests that TV117-FM may have a therapeutic role to play in the treatment of hepatocellular carcinoma. Studies are currently underway to elucidate the exact in vitro mechanism of action of this novel, metal-based anti-cancer agent.
Centre for Pharmaceutical Research and Development, Institute of Technology Tallaght, Dublin 24, Ireland. brian.duff@ittdublin.ie
Brian
B
Duff
Venkat Reddy
VR
Thangella
Bernadette S
BS
Creaven
Maureen
M
Walsh
Denise A
DA
Egan
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003300:Copper / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006224:Cricetinae; D003412:Cricetulus; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D016296:Mutagenesis / Q000187:drug effects* / Q000502:physiology; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012545:Schiff Bases / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D015363:Quinolones; D012545:Schiff Bases; D003300:Copper