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

Serena Pillozzi, Massimo D'Amico, Gianluca Bartoli, Luca Gasparoli, Giulia Petroni, Olivia Crociani, Tiziano Marzo, Angela Guerriero, Luigi Messori, Mirko Severi, Roberto Udisti, Heike Wulff, K. George Chandy, Andrea Becchetti, Annarosa Arcangeli

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)200-212
Number of pages13
JournalBritish Journal of Cancer
Volume118
Issue number2
DOIs
StatePublished - Jan 1 2018

Fingerprint

Cisplatin
Colorectal Neoplasms
Riluzole
Platinum
Apoptosis
Cell Cycle
Cell Proliferation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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.

In: British Journal of Cancer, Vol. 118, No. 2, 01.01.2018, p. 200-212.

Research output: Contribution to journalArticle

Pillozzi, S, D'Amico, M, Bartoli, G, Gasparoli, L, Petroni, G, Crociani, O, Marzo, T, Guerriero, A, Messori, L, Severi, M, Udisti, R, Wulff, H, Chandy, KG, Becchetti, A & Arcangeli, A 2018, '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', British Journal of Cancer, vol. 118, no. 2, pp. 200-212. https://doi.org/10.1038/bjc.2017.392
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. In: British Journal of Cancer. 2018 ; Vol. 118, No. 2. pp. 200-212.
@article{deef9e47c32648cd90721807e14c9e15,
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",
abstract = "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.",
author = "Serena Pillozzi and Massimo D'Amico and Gianluca Bartoli and Luca Gasparoli and Giulia Petroni and Olivia Crociani and Tiziano Marzo and Angela Guerriero and Luigi Messori and Mirko Severi and Roberto Udisti and Heike Wulff and Chandy, {K. George} and Andrea Becchetti and Annarosa Arcangeli",
year = "2018",
month = "1",
day = "1",
doi = "10.1038/bjc.2017.392",
language = "English (US)",
volume = "118",
pages = "200--212",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - 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

AU - Pillozzi, Serena

AU - D'Amico, Massimo

AU - Bartoli, Gianluca

AU - Gasparoli, Luca

AU - Petroni, Giulia

AU - Crociani, Olivia

AU - Marzo, Tiziano

AU - Guerriero, Angela

AU - Messori, Luigi

AU - Severi, Mirko

AU - Udisti, Roberto

AU - Wulff, Heike

AU - Chandy, K. George

AU - Becchetti, Andrea

AU - Arcangeli, Annarosa

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85041082898&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041082898&partnerID=8YFLogxK

U2 - 10.1038/bjc.2017.392

DO - 10.1038/bjc.2017.392

M3 - Article

C2 - 29161243

AN - SCOPUS:85041082898

VL - 118

SP - 200

EP - 212

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 2

ER -