Showing papers in "Letters in Drug Design & Discovery in 2016"

In Vitro and In Vivo Investigations into the Carbene Gold Chloride and Thioglucoside Anticancer Drug Candidates NHC-AuCl and NHC-AuSR

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.

Estrogen catechols detection as biomarkers in schistosomiasis induced cancer and infertility.

Abstract: Urogenital schistosomiasis is a chronic infection caused by the human blood fluke Schistosoma haematobium. Schistosomiasis haematobium is a known risk factor for cancer leading to squamous cell carcinoma of the urinary bladder (SCC). This is a neglected tropical disease endemic in many countries of Africa and the Middle East. Schistosome eggs produce catechol-estrogens. These molecules are metabolized to active quinones that cause alterations in DNA (leading in other contexts to breast or thyroid cancer). Our group have shown that schistosome egg associated catechol estrogens induce tumor-like phenotypes in urothelial cells, originated from parasite estrogen-host cell chromosomal DNA adducts and mutations. Here we review recent findings on the role of estrogen-DNA adducts and how their shedding in urine may be prognostic of schistosome infection and/or represent potential biomarkers for urogenital schistosomiasis associated bladder cancer and infertility.