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The metal-coordinated Casiopeína IIIEa induces the petite-like phenotype in Saccharomyces cerevisiae

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Abstract

The Casiopeínas® are mixed chelate copper (II) complexes and promising antineoplastics agents against cancer cells and tumors in vitro and in vivo. However, the action mode of these compounds is poorly characterized. In this work the effect of the antineoplastic Casiopeína IIIEa on the metabolism and ultrastructure of the yeast Saccharomyces cerevisiae was investigated. Exposure of cells growing in rich or in low-iron medium to 5 μM of the compound decreased duplication time and reduced oxygen consumption. Those cells formed smaller colonies when growing in a non-fermentable carbon source and low-iron medium, and under the light microscope, multiple folds were observed along the plasma membrane accompanied with a reduction in the diameter of the yeast. These observations were confirmed under the electron microscope, which also revealed a slight reduction of the mitochondrial size. A correlation was found with smaller colonies exhibiting lower rates of oxygen consumption, and yeast labelled with fluorescent MitoTrackerTM consistently exhibited reduced mitochondrial activity. It appears that Casiopeína IIIEa gives rise to smaller yeast and petite-like colonies by reducing the mitochondrial respiratory activity without significantly affecting the mitochondrial structure.

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Acknowledgments

This work was supported by grants from CONACYT 101851 (M-T, A.), CONACYT-REDES 87806 and PICSA10-61 (R-A, L. and M, C.) México. We thank Ruiz-Alcíbar E. for his technical support and Ma Elena Bravo–Gómez for the synthesis of Cas IIIEa. R. Gaxiola (Arizona State University) kindly donated yeast strains.

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Authors and Affiliations

  1. Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, UNAM-Campus Juriquilla, Boulevard Juriquilla 3001, C.P. 76230, Juriquilla, Querétaro, México

    Angélica López-Rodríguez, Alfonso Cárabez-Trejo, Fernando Rosas-Sánchez, Ricardo Miledi & Ataúlfo Martínez-Torres

  2. Instituto de Investigaciones Biomédicas, UNAM y, México D.F., México

    Carmen Mejía

  3. Departamento de Química Inorgánica y Nuclear, Facultad de Química, UNAM, México D.F., México

    Lena Ruiz-Azuara

  4. Molecular Neurophysiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA

    Angélica López-Rodríguez

Authors
  1. Angélica López-Rodríguez
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  2. Alfonso Cárabez-Trejo
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  3. Fernando Rosas-Sánchez
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  4. Carmen Mejía
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  5. Lena Ruiz-Azuara
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  6. Ricardo Miledi
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  7. Ataúlfo Martínez-Torres
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Corresponding authors

Correspondence to Angélica López-Rodríguez or Ataúlfo Martínez-Torres.

Electronic supplementary material

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10534_2011_9477_MOESM1_ESM.ppt

Oxymetric record showing the effect of Cas IIIEa in pre-incubated yeast. Yeast was pre-incubated for 2 h in 100 mM of Cas IIIEa and glucose (10 mM). In 20 × 106 cells, oxygen consumption was 88.2 nAtO/min and decreased to 26.46 nAtO/min after adding 100 mM of Cas IIIEa. Addition of sodium dithionite crystals reduced remaining O2. (PPT 78 kb)

10534_2011_9477_MOESM2_ESM.ppt

Effect of Cas IIIEa in spheroplasts. Over spheroplast preparation (according to Martínez-Muñoz and Peña 2005) using glutamate and malate 10 mM as substrate oxygen consumption was 8 nAt O/min. An increase in respiration (16.8 and 132 nAt O) was evidenced after adding FCCP 3 nM and Cas IIIEa (100 mM) respectively. In order to discard the site I we added 1 mg/ml of rotenone showing that it was insensible (130.67 nAt O). Addition of sodium dithionite crystals reduced remaining O2. (PPT 61 kb)

10534_2011_9477_MOESM3_ESM.ppt

Effect of Cas IIIEa on oxygen consumption rate in isolated liver rat mitochondria. The basal oxygen consumption using glutamate and malate 10 mM was 26.41 nAtO/min, after adding ADP 20 mM (107.8 nAt O) afterward Cas IIIEa (100 mM) addition (112.7 nAtO/min) first 1.5 min and then a reduction was observed (42.14 nAt O) and adding different substrates as succinate 10 mM (27.44 nAt O) and FCCP 3 nM (19.6 nAt O) respiratory activity continue decreasing. (PPT 90 kb)

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López-Rodríguez, A., Cárabez-Trejo, A., Rosas-Sánchez, F. et al. The metal-coordinated Casiopeína IIIEa induces the petite-like phenotype in Saccharomyces cerevisiae . Biometals 24, 1189–1196 (2011). https://doi.org/10.1007/s10534-011-9477-7

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