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| Item Type: | Article |
|---|---|
| Title: | In vitro and in vivo investigations into the carbene gold chloride and thioglucoside anticancer drug candidates NHC-AuCl and NHC-AuSR |
| Creators Name: | Walther, W. and Dada, O. and O’Beirne, C. and Ott, I. and Sanchez-Sanz, G. and Schmidt, C. and Werner, C. and Zhu, X. and Tacke, M. |
| Abstract: | The anticancer drug candidate 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) chloride (NHC-AuCl) and its 2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl-1'-thiolate derivative (NHC-AuSR), which is a potential ligand for glucose transporters, were tested on the NCI 60 cancer cell panel in vitro. NHC-AuCl and NHC-AuSR showed very good activity against a wide range of human cancer cell lines inclusive renal cell cancer with similar average GI50 values of 1.78 and 1.95 μM, respectively. This encouraged maximum tolerable dose (MTD) experiments in mice, where MTD values of 10 mg/kg for NHC-AuCl and 7.5 mg/kg for NHC-AuSR were determined with single injections to groups of 2 mice. In the following tumor xenograft experiment NHC-AuCl and NHC-AuSR were given at MTD in 6 injections to two cohorts of 6 CAKI-1 tumor-bearing NMRI:nu/nu mice, while a control cohort of 6 mice was treated with solvent only. NHC-AuCl at the dose of 10 mg/kg and NHC-AuSR at the lower dose of 7.5 mg/kg induced both low toxicities in the form of abdominal swelling but no significant body weight loss was seen in both groups. The tumor volume growth reduction was significant and almost identical; optimal T/C values of 0.47 were observed on day 19 for NHC-AuCl and on day 29 for NHC-AuSR. Immunohistochemistry for the proliferation marker Ki-67 and the angiogenesis marker CD31 did not show significant changes due to NHC-AuCl or NHC-AuSR treatment in the animals. However, thioredoxin reductase (TrxR) inhibition with IC50 values of 1.5 μM for NHC-AuCl and 3.1 μM for NHC-AuSR seems to indicate that apoptosis induction through elevated oxidative stress is the main mechanism for the two gold compounds. |
| Keywords: | Carbene-Gold Anticancer Drug, NCI 60 Cancer Cell Panel, Thioredoxin Reductase, CAKI-1 Renal Cell Cancer, Xenograft Mouse Model, Glucose Transporter, Animals, Mice |
| Source: | Letters in Drug Design & Discovery |
| ISSN: | 1570-1808 |
| Publisher: | Bentham |
| Volume: | 14 |
| Number: | 2 |
| Page Range: | 125-134 |
| Date: | 2017 |
| Additional Information: | Copyright © 2017 Bentham Science Publishers. This article is made available under the Creative Commons Attribution 4.0 International Public License CC-BY 4.0. To view a copy of this license, visit https://creativecommons.org/licenses/by-nc/4.0/ or send a letter to Creative Commons, PO Box 1866, Mountain View, CA 94042, USA. |
| Official Publication: | https://doi.org/10.2174/1570180813666160826100158 |
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