Issue 9, 2015

Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo

Abstract

Following recent work on heterometallic titanocene–gold complexes as potential chemotherapeutics for renal cancer, we report here on the synthesis, characterization and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = S–C6H4–COO) bound to gold(I)-phosphane fragments through a thiolate group [(η-C5H5)2TiMe(μ-mba)Au(PR3)]. The compounds are more stable in physiological media than those previously reported and are highly cytotoxic against human cancer renal cell lines. We describe here preliminary mechanistic data involving studies on the interaction of selected compounds with plasmid (pBR322) DNA used as a model nucleic acid, and with selected protein kinases from a panel of 35 protein kinases having oncological interest. Preliminary mechanistic studies in Caki-1 renal cells indicate that the cytotoxic and anti-migration effects of the most active compound 5 [(η-C5H5)2TiMe(μ-mba)Au(PPh3)] involve inhibition of thioredoxin reductase and loss of expression of protein kinases that drive cell migration (AKT, p90-RSK, and MAPKAPK3). The co-localization of both titanium and gold metals (1 : 1 ratio) in Caki-1 renal cells was demonstrated for 5 indicating the robustness of the heterometallic compound in vitro. Two compounds were selected for further in vivo studies on mice based on their selectivity in vitro against renal cancer cell lines when compared to non-tumorigenic human kidney cell lines (HEK-293T and RPTC) and the favourable preliminary toxicity profile in C57BL/6 mice. Evaluation of Caki-1 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (67%) after treatment for 28 days (3 mg per kg per every other day) with heterometallic compound 5 as compared with the previously described [(η-C5H5)2Ti{OC(O)-4-C6H4-P(Ph2)AuCl}2] 3 which was non-inhibitory. These findings indicate that structural modifications on the ligand scaffold affect the in vivo efficacy of this class of compounds.

Graphical abstract: Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo

Supplementary files

Article information

Article type
Edge Article
Submitted
13 May 2015
Accepted
23 Jun 2015
First published
23 Jun 2015
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2015,6, 5269-5283

Author version available

Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo

J. Fernández-Gallardo, B. T. Elie, T. Sadhukha, S. Prabha, M. Sanaú, S. A. Rotenberg, J. W. Ramos and M. Contel, Chem. Sci., 2015, 6, 5269 DOI: 10.1039/C5SC01753J

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