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In vitro and in vivo investigations into the carbene silver acetate anticancer drug candidate SBC1

Item Type:Article
Title:In vitro and in vivo investigations into the carbene silver acetate anticancer drug candidate SBC1
Creators Name:Fichtner, I. and Cinatl, J. and Michaelis, M. and Sanders, L.C. and Hilger, R. and Kennedy, B.N. and Reynolds, A.L. and Hackenberg, F. and Lally, G. and Quinn, S.J. and McRae, I. and Tacke, M.
Abstract: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 {Mu}M; 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 {Mu}M, 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 {Delta}G 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, DNA-Binding Assay, Xenograft Mouse Model, Zebrafish Intersegmental Vessel Assay, Animals, Mice, Zebrafish
Source:Letters in Drug Design & Discovery
ISSN:1570-1808
Publisher:Bentham (U.K.)
Volume:9
Number:9
Page Range:815-822
Date:November 2012
Official Publication:https://doi.org/10.2174/157018012803307987

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