Letters in Drug Design & Discovery

G. Perry
University of Texas
San Antonio, TX
Email: lddd@benthamscience.org


In Vitro and In Vivo Investigations into the Carbene Silver Acetate Anticancer Drug Candidate SBC1

Author(s): Iduna Fichtner, Jindrich Cinatl, Martin Michaelis, Lara C. Sanders, Ralf Hilger, Breandan N. Kennedy, Alison L. Reynolds, Frauke Hackenberg, Grainne Lally, Susan J. Quinn, Ian McRae, Matthias Tacke.


The anticancer drug candidate (1-methyl-3-(p-cyanobenzyl)benzimidazole-2-ylidene)silver(I)acetate (SBC1) was tested in vitro against human neuroblastoma cells, UKF-NB-3 and UKF-NB-6, delivering IC50 values of 29 +/- 5 and 29 +/- 4 μM, while further testing against cisplatin-, carboplatin- and oxaliplatin-resistant UKF-NB-3/6 sub-lines showed no cross-resistance with respect to SBC1. A similar trend was found for SBC1 against the human colon carcinoma cell line HCT8 with an IC50 value of 3.1 +/- 0.9 μM; SBC1 was again able to break cisplatin- and carboplatin-resistance in the corresponding sub-lines. SBC1 was also tested against the prostate cancer cell line PC-3 and its paclitaxel-resistant sub-line, which gave IC50 values of 14.1 +/- 0.9 and 14.5 +/- 0.8 μM, which indicated no cross-resistance with paclitaxel. In order to test the possible transport of SBC1 via albumin the binding of SBC1 against this transport protein was measured using a fluorescence titration, which gave an ΔG value of 28 +/- 3 kJ/mol. In circular dichroism and DNA denaturation assays SBC1 proved to be a strongly DNA-binding drug candidate. SBC1 was then given at 25 and 50 mg/kg/d, in four injections to two cohorts of eight CAKI-1 tumor-bearing NMRI:nu/nu mice, while a further cohort was treated with solvent only. At these two dosages SBC1 showed a borderline toxicity leading to mortality and body weight loss, while no significant tumor growth reduction or influence on blood parameter with respect to the solvent-treated control group was observed. Further in vivo testing against zebrafish larvae revealed significant toxicity of SBC1 at micromolar concentrations; no useable anti-angiogenic dosage was observed.

Keywords: Anticancer drug, Anti-angiogenic drug, Carbene-silver complex, Renal cell cancer, Albumin-binding assay, DNAbinding assay, Xenograft mouse model, Zebrafish intersegmental vessel assay

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Article Details

Year: 2012
Page: [815 - 822]
Pages: 8
DOI: 10.2174/157018012803307987
Price: $58