Cytotoxicity, apoptosis and study of the DNA-binding properties of bi- and tetranuclear gallium(III) complexes with heterocyclic thiolato ligands

• Published in: Investigational new drugs 2011-10, Vol.29 (5), p.932-944
• Main Authors: Gallego, Beatriz, Kaluđerović, Milena R., Kommera, Harish, Paschke, Reinhard, Hey-Hawkins, Evamarie, Remmerbach, Torsten W., Kaluđerović, Goran N., Gómez-Ruiz, Santiago
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - drug effects; Cancer therapies; Caspases - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Chemotherapy; Crystallography, X-Ray; Cytotoxicity; DNA - metabolism; DNA Fragmentation - drug effects; Drug Screening Assays, Antitumor; Drugs; Gallium - pharmacology; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Humans; Inhibitory Concentration 50; Ligands; Medicine; Medicine & Public Health; Models, Molecular; Nitrates; Oncology; Ovarian cancer; Pharmacology; Pharmacology/Toxicology; Plasmids - genetics; Preclinical Studies; Spectrophotometry, Ultraviolet; Studies; Sulfhydryl Compounds - chemical synthesis; Sulfhydryl Compounds - chemistry; Sulfhydryl Compounds - pharmacology; Thyroid cancer
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-010-9449-8

Summary The reaction of the heterocyclic thiol derivatives, 2-mercapto-1-methylimidazole (SH-imi), 5-mercapto-1-methyltetrazole (SH-tet), 2-mercaptobenzothiazole (SH-ben) and 5-phenyl-1,3,4-oxadiazole-2-thiol (SH-oxa), with trimethylgallium (1:1) afforded the dimeric or tetrameric complexes [Me 2 Ga(S-imi)] 2 ( 1 ), [Me 2 Ga(S-tet)] 2 ( 2 ), [Me 2 Ga(S-ben)] 2 ( 3 ) and [Me 2 Ga(S-oxa)] 4 ( 4 ), respectively. Molecular structures of 2 and 4 were determined by X-ray diffraction studies. The cytotoxicity of the gallium(III) complexes 1 – 4 was tested against human cell lines 8505C anaplastic thyroid cancer, A253 head and neck tumor, A549 lung carcinoma, A2780 ovarian cancer, DLD-1 colon carcinoma and compared with those of cisplatin and Ga(NO 3 ) 3 . Compound 4 seems to be slightly more active against 8505C, A253 and A2780 and substantially more active than all the other complexes against DLD-1, with an IC 50 value of 5.49 ± 0.16 µM, very close to that of cisplatin (5.14 ± 0.12 µM). Complexes 1 – 4 were less toxic on normal human fibroblasts (WWO70327) than on the investigated tumor cell lines and more selective to cancer cells than cisplatin. DNA laddering method showed that treatment of the DLD-1 cell line with IC 90 doses of 1 – 4 resulted in the induction of apoptosis. Compound 1 caused apoptosis by upregulation of caspases 2, 3 and 8. Since no activity of caspase 9 is observed, complex 1 is causing apoptosis triggered by an extrinsic pathway. DNA-interaction tests have been also carried out. Solutions of all the studied complexes have been treated with different concentrations of fish sperm DNA (FS-DNA). Modifications of the UV spectra which gave intrinsic binding constants of 3.03 × 10 5 , 4.44 × 10 5 , 3.02 × 10 6 and 5.56 × 10 5  M −1 for 1 – 4 were observed, however, no notable interaction with pBR322 plasmid DNA was detected.