TY - JOUR
T1 - Multiple effects of the Na+/H+ antiporter inhibitor HMA on cancer cells
AU - Aredia, Francesca
AU - Giansanti, Vincenzo
AU - Mazzini, Giuliano
AU - Savio, Monica
AU - Ortiz, Luis Miguel Guamán
AU - Jaadane, Imène
AU - Zaffaroni, Nadia
AU - Forlino, Antonella
AU - Torriglia, Alicia
AU - Scovassi, Anna Ivana
PY - 2013/12
Y1 - 2013/12
N2 - 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.
AB - 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.
KW - Amiloride
KW - Apoptosis
KW - Autophagy
KW - LEI/L-DNase II
KW - MDR
KW - Parthanatos
UR - http://www.scopus.com/inward/record.url?scp=84889084214&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84889084214&partnerID=8YFLogxK
U2 - 10.1007/s10495-013-0898-3
DO - 10.1007/s10495-013-0898-3
M3 - Article
C2 - 23996609
AN - SCOPUS:84889084214
VL - 18
SP - 1586
EP - 1598
JO - Apoptosis : an international journal on programmed cell death
JF - Apoptosis : an international journal on programmed cell death
SN - 1360-8185
IS - 12
ER -