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Multiple effects of the Na+/H+ antiporter inhibitor HMA on cancer cells

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Abstract

Amiloride derivatives are a class of new promising chemotherapeutic agents. A representative member of this family is the sodium–hydrogen antiporter inhibitor HMA (5-(N,N-hexamethylene amiloride), which has been demonstrated to induce cellular intracytosolic acidification and cell death through the apoptotic pathway(s). This work aims at characterizing drug response of human cancer cell lines to HMA. After a first screening revealing that HMA interferes with cancer cell survival, we focused our attention on SW613-B3 colon carcinoma cells, which are intrinsically resistant to a panel of drugs. Searching for the activation of canonical apoptosis, we found that this process was abortive, given that the final steps of this process, i.e. PARP-1 cleavage and DNA ladder, were not detectable. Thus, we addressed caspase-independent paradigms of cell death and we observed that HMA promotes the induction of the LEI/L-DNase II pathway as well as of parthanatos. Finally, we explored the possible impact of autophagy of cell response to HMA, providing the evidence that autophagy is activated in our experimental system. On the whole, our results defined the biochemical reactions triggered by HMA, and elucidated its multiple effects, thus adding further complexity to the intricate network leading to drug resistance.

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Acknowledgments

We are indebted to Maria Grazia Bottone for cytoskeleton immunofluorescence, Roberta Gioia for qPCR analysis and Marzia Pennati for survivin experiments. Research was partially granted by Italian Regione Lombardia (Project Plant Cell to A.I.S) and Cariplo (Project 2011-0270 to A.F.). F.A. is a PhD student (Dottorato in Genetica, Biologia Cellulare e Molecolare, University of Pavia, Italy). L.M.G.O. is a PhD student (Dottorato in Genetica, Biologia Cellulare e Molecolare, University of Pavia, Italy) supported by SENESCYT (Quito, Ecuador) and UTPL (Loja, Ecuador). I.J. is supported by an ADEME grant to A.T.

Conflict of interest

None declared.

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Authors and Affiliations

  1. Istituto di Genetica Molecolare CNR, 27100, Pavia, Italy

    Francesca Aredia, Vincenzo Giansanti, Giuliano Mazzini, Luis Miguel Guamán Ortiz & Anna Ivana Scovassi

  2. Dipartimento di Medicina Molecolare, sez. Patologia Generale, Università di Pavia, 27100, Pavia, Italy

    Monica Savio

  3. Departamento de Ciencias de la Salud, UTPL, 11-01-608, Loja, Ecuador

    Luis Miguel Guamán Ortiz

  4. Centre de Recherches des Cordeliers, INSERM, U872 éq. 17, 75006, Paris, France

    Imène Jaadane & Alicia Torriglia

  5. Université Pierre et Marie Curie Paris 6, 75006, Paris, France

    Imène Jaadane & Alicia Torriglia

  6. Université Paris Descartes, 75006, Paris, France

    Imène Jaadane & Alicia Torriglia

  7. Fondazione IRCCS Istituto Nazionale Tumori, 20133, Milan, Italy

    Nadia Zaffaroni

  8. Dipartimento di Biochimica, Università di Pavia, 27100, Pavia, Italy

    Antonella Forlino

Authors
  1. Francesca Aredia
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  2. Vincenzo Giansanti
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  3. Giuliano Mazzini
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  4. Monica Savio
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  5. Luis Miguel Guamán Ortiz
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  6. Imène Jaadane
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  7. Nadia Zaffaroni
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  8. Antonella Forlino
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  9. Alicia Torriglia
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  10. Anna Ivana Scovassi
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Corresponding author

Correspondence to Anna Ivana Scovassi.

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Aredia, F., Giansanti, V., Mazzini, G. et al. Multiple effects of the Na+/H+ antiporter inhibitor HMA on cancer cells. Apoptosis 18, 1586–1598 (2013). https://doi.org/10.1007/s10495-013-0898-3

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  • DOI: https://doi.org/10.1007/s10495-013-0898-3

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