In vitro anti-tumour and cyto-selective effects of coumarin-3-carboxylic acid and three of its hydroxylated derivatives, along with their silver-based complexes, using human epithelial carcinoma cell lines.
The chemotherapeutic potential of coumarin-3-carboxylic acid (C-3-COOH) and a series of three hydroxylated coumarin-3-carboxylic acid ligands, namely 6-hydroxy-coumarin-3-carboxylic acid (6-OH-C-3-COOH), 7-hydroxy-coumarin-3-carboxylic acid (7-OH-C-3-COOH) and 8-hydroxy-coumarin-3-carboxylic acid (8-OH-C-3-COOH), along with their corresponding silver-based complexes, namely 6-hydroxycoumarin-3-carboxylatosilver (6-OH-C-COO-Ag), 7-hydroxycoumarin-3-carboxylatosilver (7-OH-C-COO-Ag) and 8-hydroxycoumarin-3-carboxylatosilver (8-OH-C-COO-Ag), was determined using two human-derived carcinoma (A-498 and Hep-G2), along with two non-carcinoma human-derived cell lines (CHANG and HK-2). All of the ligands and their silver complexes induced a concentration-dependent cytotoxic effect. Furthermore, hydroxylation of C-3-COOH and its subsequent complexation with silver led to the production of a series of compounds with dramatically enhanced cytotoxicity, with 6-OH-C-3-COO-Ag having the greatest activity. Additionally, all of the metal-based complexes were selectively cytotoxic to both carcinoma-derived cell lines, relative to normal renal and hepatic cells. In comparative studies with cisplatin, and based on the IC(50) values obtained with Hep-G2 cells, it appeared that the coumarin-silver complexes were between 2 and 5.5 times more cytotoxic than cisplatin. All of the coumarin-silver complexes inhibited DNA synthesis, which did not appear to be mediated through intercalation. Furthermore, results obtained from Ames tests showed that all of the test agents and their phase I metabolites were non-mutagenic. Taken together, these findings suggest that both hydroxylation particularly in the 6th position and complexation with silver, served to significantly augment the cytotoxic properties of C-3-COOH, to yield a compound which acts as a cyto-selective agent, as it is a significant killer of cancer, relative to normal cells. We suggest that this group of compounds may have a therapeutic role to play in the successful treatment and management of cancer in man.
Thati
Bhumika
B
Centre for Pharmaceutical R&D, School of Science, Institute of Technology, Tallaght, Dublin 24, Ireland.
Noble
Andy
A
Creaven
Bernadette S
BS
Walsh
Maureen
M
McCann
Malachy
M
Kavanagh
Kevin
K
Devereux
Michael
M
Egan
Denise A
DA
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D009152:Mutagenicity Tests; D018030:Silver Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D003374:Coumarins; D018030:Silver Compounds; D004247:DNA; C104227:coumarin-3-carboxylic acid