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The combined activation of K(Ca)3.1 and inhibition of K(v)11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells

BACKGROUND: Platinum-based drugs such as Cisplatin are commonly employed for cancer treatment. Despite an initial therapeutic response, Cisplatin treatment often results in the development of chemoresistance. To identify novel approaches to overcome Cisplatin resistance, we tested Cisplatin in combi...

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Autores principales: Pillozzi, Serena, D'Amico, Massimo, Bartoli, Gianluca, Gasparoli, Luca, Petroni, Giulia, Crociani, Olivia, Marzo, Tiziano, Guerriero, Angela, Messori, Luigi, Severi, Mirko, Udisti, Roberto, Wulff, Heike, Chandy, K George, Becchetti, Andrea, Arcangeli, Annarosa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785745/
https://www.ncbi.nlm.nih.gov/pubmed/29161243
http://dx.doi.org/10.1038/bjc.2017.392
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author Pillozzi, Serena
D'Amico, Massimo
Bartoli, Gianluca
Gasparoli, Luca
Petroni, Giulia
Crociani, Olivia
Marzo, Tiziano
Guerriero, Angela
Messori, Luigi
Severi, Mirko
Udisti, Roberto
Wulff, Heike
Chandy, K George
Becchetti, Andrea
Arcangeli, Annarosa
author_facet Pillozzi, Serena
D'Amico, Massimo
Bartoli, Gianluca
Gasparoli, Luca
Petroni, Giulia
Crociani, Olivia
Marzo, Tiziano
Guerriero, Angela
Messori, Luigi
Severi, Mirko
Udisti, Roberto
Wulff, Heike
Chandy, K George
Becchetti, Andrea
Arcangeli, Annarosa
author_sort Pillozzi, Serena
collection PubMed
description BACKGROUND: Platinum-based drugs such as Cisplatin are commonly employed for cancer treatment. Despite an initial therapeutic response, Cisplatin treatment often results in the development of chemoresistance. To identify novel approaches to overcome Cisplatin resistance, we tested Cisplatin in combination with K(+) channel modulators on colorectal cancer (CRC) cells. METHODS: The functional expression of Ca(2+)-activated (K(Ca)3.1, also known as KCNN4) and voltage-dependent (K(v)11.1, also known as KCNH2 or hERG1) K(+) channels was determined in two CRC cell lines (HCT-116 and HCT-8) by molecular and electrophysiological techniques. Cisplatin and several K(+) channel modulators were tested in vitro for their action on K(+) currents, cell vitality, apoptosis, cell cycle, proliferation, intracellular signalling and Platinum uptake. These effects were also analysed in a mouse model mimicking Cisplatin resistance. RESULTS: Cisplatin-resistant CRC cells expressed higher levels of K(Ca)3.1 and K(v)11.1 channels, compared with Cisplatin-sensitive CRC cells. In resistant cells, K(Ca)3.1 activators (SKA-31) and K(v)11.1 inhibitors (E4031) had a synergistic action with Cisplatin in triggering apoptosis and inhibiting proliferation. The effect was maximal when K(Ca)3.1 activation and K(v)11.1 inhibition were combined. In fact, similar results were produced by Riluzole, which is able to both activate K(Ca)3.1 and inhibit K(v)11.1. Cisplatin uptake into resistant cells depended on K(Ca)3.1 channel activity, as it was potentiated by K(Ca)3.1 activators. K(v)11.1 blockade led to increased K(Ca)3.1 expression and thereby stimulated Cisplatin uptake. Finally, the combined administration of a K(Ca)3.1 activator and a K(v)11.1 inhibitor also overcame Cisplatin resistance in vivo. CONCLUSIONS: As Riluzole, an activator of K(Ca)3.1 and inhibitor of K(v)11.1 channels, is in clinical use, our results suggest that this compound may be useful in the clinic to improve Cisplatin efficacy and overcome Cisplatin resistance in CRC.
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spelling pubmed-57857452019-01-01 The combined activation of K(Ca)3.1 and inhibition of K(v)11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells Pillozzi, Serena D'Amico, Massimo Bartoli, Gianluca Gasparoli, Luca Petroni, Giulia Crociani, Olivia Marzo, Tiziano Guerriero, Angela Messori, Luigi Severi, Mirko Udisti, Roberto Wulff, Heike Chandy, K George Becchetti, Andrea Arcangeli, Annarosa Br J Cancer Translational Therapeutics BACKGROUND: Platinum-based drugs such as Cisplatin are commonly employed for cancer treatment. Despite an initial therapeutic response, Cisplatin treatment often results in the development of chemoresistance. To identify novel approaches to overcome Cisplatin resistance, we tested Cisplatin in combination with K(+) channel modulators on colorectal cancer (CRC) cells. METHODS: The functional expression of Ca(2+)-activated (K(Ca)3.1, also known as KCNN4) and voltage-dependent (K(v)11.1, also known as KCNH2 or hERG1) K(+) channels was determined in two CRC cell lines (HCT-116 and HCT-8) by molecular and electrophysiological techniques. Cisplatin and several K(+) channel modulators were tested in vitro for their action on K(+) currents, cell vitality, apoptosis, cell cycle, proliferation, intracellular signalling and Platinum uptake. These effects were also analysed in a mouse model mimicking Cisplatin resistance. RESULTS: Cisplatin-resistant CRC cells expressed higher levels of K(Ca)3.1 and K(v)11.1 channels, compared with Cisplatin-sensitive CRC cells. In resistant cells, K(Ca)3.1 activators (SKA-31) and K(v)11.1 inhibitors (E4031) had a synergistic action with Cisplatin in triggering apoptosis and inhibiting proliferation. The effect was maximal when K(Ca)3.1 activation and K(v)11.1 inhibition were combined. In fact, similar results were produced by Riluzole, which is able to both activate K(Ca)3.1 and inhibit K(v)11.1. Cisplatin uptake into resistant cells depended on K(Ca)3.1 channel activity, as it was potentiated by K(Ca)3.1 activators. K(v)11.1 blockade led to increased K(Ca)3.1 expression and thereby stimulated Cisplatin uptake. Finally, the combined administration of a K(Ca)3.1 activator and a K(v)11.1 inhibitor also overcame Cisplatin resistance in vivo. CONCLUSIONS: As Riluzole, an activator of K(Ca)3.1 and inhibitor of K(v)11.1 channels, is in clinical use, our results suggest that this compound may be useful in the clinic to improve Cisplatin efficacy and overcome Cisplatin resistance in CRC. Nature Publishing Group 2018-01 2017-11-21 /pmc/articles/PMC5785745/ /pubmed/29161243 http://dx.doi.org/10.1038/bjc.2017.392 Text en Copyright © 2018 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/4.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
spellingShingle Translational Therapeutics
Pillozzi, Serena
D'Amico, Massimo
Bartoli, Gianluca
Gasparoli, Luca
Petroni, Giulia
Crociani, Olivia
Marzo, Tiziano
Guerriero, Angela
Messori, Luigi
Severi, Mirko
Udisti, Roberto
Wulff, Heike
Chandy, K George
Becchetti, Andrea
Arcangeli, Annarosa
The combined activation of K(Ca)3.1 and inhibition of K(v)11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells
title The combined activation of K(Ca)3.1 and inhibition of K(v)11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells
title_full The combined activation of K(Ca)3.1 and inhibition of K(v)11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells
title_fullStr The combined activation of K(Ca)3.1 and inhibition of K(v)11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells
title_full_unstemmed The combined activation of K(Ca)3.1 and inhibition of K(v)11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells
title_short The combined activation of K(Ca)3.1 and inhibition of K(v)11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells
title_sort combined activation of k(ca)3.1 and inhibition of k(v)11.1/herg1 currents contribute to overcome cisplatin resistance in colorectal cancer cells
topic Translational Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785745/
https://www.ncbi.nlm.nih.gov/pubmed/29161243
http://dx.doi.org/10.1038/bjc.2017.392
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