2. Academic Validation
  3. The combined activation of KCa3.1 and inhibition of Kv11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells

The combined activation of KCa3.1 and inhibition of Kv11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells

  • Br J Cancer. 2018 Jan;118(2):200-212. doi: 10.1038/bjc.2017.392.
Serena Pillozzi 1,  Massimo D'Amico 2,  Gianluca Bartoli 1,  Luca Gasparoli 1,  Giulia Petroni 1,  Olivia Crociani 1,  Tiziano Marzo 3 4,  Angela Guerriero 1,  Luigi Messori 3,  Mirko Severi 5,  Roberto Udisti 5,  Heike Wulff 6,  K George Chandy 7,  Andrea Becchetti 8,  Annarosa Arcangeli 1
Affiliations

Affiliations

  • 1 Department of Experimental and Clinical Medicine, Section of Internal Medicine, University of Florence, Viale G.B. Morgagni 50, 50134 Firenze, Italy.
  • 2 DIVAL Toscana Srl, Via Madonna del Piano 6, Sesto Fiorentino, 50119 Firenze, Italy.
  • 3 Laboratory of Metals in Medicine (MetMed), Department of Chemistry, University of Florence, Via della Lastruccia 3, Sesto Fiorentino, 50019 Florence, Italy.
  • 4 Department of Chemistry and Industrial Chemistry (DCCI), University of Pisa, Via Moruzzi 13, 56124 Pisa, Italy.
  • 5 Department of Chemistry, University of Florence, Via della Lastruccia 3, Sesto Fiorentino, 50019 Florence, Italy.
  • 6 Department of Pharmacology, 451 Health Sciences Drive, University of California, Davis, CA 95616, USA.
  • 7 Laboratory of Molecular Physiology in the Infection and Immunity Theme, Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore.
  • 8 Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy.
PMID: 29161243 DOI: 10.1038/bjc.2017.392
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 Ca2+-activated (KCa3.1, also known as KCNN4) and voltage-dependent (Kv11.1, 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 KCa3.1 and Kv11.1 channels, compared with Cisplatin-sensitive CRC cells. In resistant cells, KCa3.1 activators (SKA-31) and Kv11.1 inhibitors (E4031) had a synergistic action with Cisplatin in triggering Apoptosis and inhibiting proliferation. The effect was maximal when KCa3.1 activation and Kv11.1 inhibition were combined. In fact, similar results were produced by Riluzole, which is able to both activate KCa3.1 and inhibit Kv11.1. Cisplatin uptake into resistant cells depended on KCa3.1 channel activity, as it was potentiated by KCa3.1 activators. Kv11.1 blockade led to increased KCa3.1 expression and thereby stimulated Cisplatin uptake. Finally, the combined administration of a KCa3.1 activator and a Kv11.1 inhibitor also overcame Cisplatin resistance in vivo.

Conclusions: As Riluzole, an activator of KCa3.1 and inhibitor of Kv11.1 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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