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

Francesca Aredia, Vincenzo Giansanti, Giuliano Mazzini, Monica Savio, Luis Miguel Guamán Ortiz, Imène Jaadane, Nadia Zaffaroni, Antonella Forlino, Alicia Torriglia, Anna Ivana Scovassi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1586-1598
Number of pages13
JournalApoptosis
Volume18
Issue number12
DOIs
Publication statusPublished - Dec 2013

Keywords

  • Amiloride
  • Apoptosis
  • Autophagy
  • LEI/L-DNase II
  • MDR
  • Parthanatos

ASJC Scopus subject areas

  • Cell Biology
  • Clinical Biochemistry
  • Biochemistry, medical
  • Cancer Research
  • Pharmaceutical Science
  • Pharmacology

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  • Cite this

    Aredia, F., Giansanti, V., Mazzini, G., Savio, M., Ortiz, L. M. G., Jaadane, I., Zaffaroni, N., Forlino, A., Torriglia, A., & Scovassi, A. I. (2013). Multiple effects of the Na+/H+ antiporter inhibitor HMA on cancer cells. Apoptosis, 18(12), 1586-1598. https://doi.org/10.1007/s10495-013-0898-3