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Analysis of the cytotoxic effects of ruthenium–ketoconazole and ruthenium–clotrimazole complexes on cancer cells

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Abstract

Ruthenium-based compounds have intriguing anti-cancer properties, and some of these novel compounds are currently in clinical trials. To continue the development of new metal-based drug combinations, we coupled ruthenium (Ru) with the azole compounds ketoconazole (KTZ) and clotrimazole (CTZ), which are well-known antifungal agents that also display anticancer properties. We report the activity of a series of 12 Ru–KTZ and Ru–CTZ compounds against three prostate tumor cell lines with different androgen sensitivity, as well as cervical cancer and lymphoblastic lymphoma cell lines. In addition, human cell lines were used to evaluate the toxicity against non-transformed cells and to establish selectivity indexes. Our results indicate that the combination of ruthenium and KTZ/CTZ in a single molecule results in complexes that are more cytotoxic than the individual components alone, displaying in some cases low micromolar CC50 values and high selectivity indexes. Additionally, all compounds are more cytotoxic against prostate cell lines with lower cytotoxicity against non-transformed epidermal cell lines. Some of the compounds were found to primarily induce cell death via apoptosis yet weakly interact with DNA. Our studies also demonstrate that the cytotoxicity induced by our Ru-based compounds is not directly related to their ability to interact with DNA.

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Acknowledgments

We thank Dr. Chuanshu Huang at New York University School of Medicine for the gift of MEFs. We also thank the Biomolecule Analysis and the Cytometry, Screening and Imaging Core Facilities at the University of Texas at El Paso, supported by RCMI program Grant No. 8G12MD007592, to the Border Biomedical Research Center, from the NIMHD-NIH. We acknowledge support from the NIGMS SCORE Grants 1SC3GM103713-01 to RJA and 1SC1GM089558 to RAS-D. ERE was supported by the RISE Scholars Program at UTEP through NIGMS Grant No. R25GM069621-10.

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  1. Border Biomedical Research Center and Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, 79968, USA

    Elisa Robles-Escajeda, Armando Varela-Ramirez & Renato J. Aguilera

  2. Chemistry Department, New York City College of Technology, The City University of New York, Brooklyn, NY, 11201, USA

    Alberto Martínez

  3. Chemistry Department of Brooklyn College and The Graduate Center, The City University of New York, Brooklyn, NY, 11210, USA

    Roberto A. Sánchez-Delgado

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  1. Elisa Robles-Escajeda
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  2. Alberto Martínez
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  3. Armando Varela-Ramirez
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  4. Roberto A. Sánchez-Delgado
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  5. Renato J. Aguilera
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Correspondence to Renato J. Aguilera.

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Elisa Robles-Escajeda and Alberto Martínez are co-first authors.

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Robles-Escajeda, E., Martínez, A., Varela-Ramirez, A. et al. Analysis of the cytotoxic effects of ruthenium–ketoconazole and ruthenium–clotrimazole complexes on cancer cells. Cell Biol Toxicol 29, 431–443 (2013). https://doi.org/10.1007/s10565-013-9264-z

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