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 combination with K+ channel modulators on colorectal cancer (CRC) cells. Methods: The functional expression of Ca2+-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 Kv11.1 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.