The combined activation of KCa3.1 and inhibition of Kv11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells
| Autor: | Massimo D'Amico, Luca Gasparoli, Mirko Severi, Tiziano Marzo, Giulia Petroni, Olivia Crociani, Gianluca Bartoli, Luigi Messori, Angela Guerriero, Heike Wulff, Serena Pillozzi, Annarosa Arcangeli, Andrea Becchetti, K. George Chandy, Roberto Udisti |
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| Přispěvatelé: | 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, K, Becchetti, A, Arcangeli, A, Lee Kong Chian School of Medicine (LKCMedicine) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Oncology Cancer Research ERG1 Potassium Channel preclinical mouse models Cell Drug Resistance Apoptosis Mice BIO/09 - FISIOLOGIA Riluzole SKA-31 E4031 Cisplatin uptake Cancer Tumor Chemistry Cell Cycle Drug Synergism Cell cycle Intermediate-Conductance Calcium-Activated Potassium Channels Colo-Rectal Cancer medicine.anatomical_structure 5.1 Pharmaceuticals Public Health and Health Services Development of treatments and therapeutic interventions Colorectal Neoplasms HT29 Cells medicine.drug medicine.medical_specialty Cell Survival Oncology and Carcinogenesis Cell Line 03 medical and health sciences KCNN4 Inhibitory Concentration 50 In vivo Internal medicine medicine Potassium Channel Blockers Animals Humans Medicine [Science] Benzothiazoles Oncology & Carcinogenesis Cisplatin Activator (genetics) HCT116 Cells 030104 developmental biology Cell culture Cancer research Pyrazoles Neoplasm cisplatin KCa hERG colorectal cancer chemoresistance Digestive Diseases |
| Zdroj: | British journal of cancer, vol 118, iss 2 |
| Popis: | 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. Published version |
| Databáze: | OpenAIRE |
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