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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.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In the present work, applying the whole-cell patch-clamp technique in voltage clamp mode, we have investigated the effects of different drugs, such as riluzole, Psora-4 and Tram-34, on the potassium currents in four human lymphoma cell lines. We focused on outward currents mediated by two potassium channels (Kv1.3 and KCa3.1), which are known to play a key physiological role in lymphoid cells. The currents were evoked by voltage ramps ranging from -120 mV to +40 mV and the conductance of the two potassium channels was measured between +20 mV and +40 mV, both in the absence and in the presence of the specific blockers Psora-4 (Kv1.3; 1 µM) and Tram-34 (KCa3.1; 1 µM). The effect of the latter was tested after KCa3.1 channels were activated by riluzole 10 µM. Taken together, these data could be useful as an indication of the functional characteristics of the potassium channels in human lymphomas and represent a starting point for the study of potassium conductance in cellular models of these tumors., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article., (© 2020 Università degli Studi di Firenze. Published by Elsevier Inc.)

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.

Objectives: The role of the lymphatic system in the connection between spondyloarthritis (SpA) and Crohn's disease (CD) remains yet to be elucidated. The aim of the present study was to investigate the circulating levels of lymphatic endothelial progenitor cells (LEPCs) and vascular endothelial growth factor-C (VEGF-C) and their possible correlation with clinical parameters in SpA, SpA associated with CD (SC), and CD., Methods: Peripheral blood samples from SpA (n=36), SC (n=20) and CD (n=28) patients and 20 age- and sex-matched healthy controls were collected and used for quantification of circulating LEPCs and VEGF-C. LEPCs were identified by fluorescence-activated cell sorting using FITC-CD34, APC-CD133 and PE-VEGFR-3 antibodies. Serum levels of VEGF-C were measured by enzyme-linked immunosorbent assay. The possible correlations between disease duration (< or >10 years; < or >20 years) and clinical activity (BASDAI for SpA or CDAI for CD) and LEPC counts and VEGF-C levels were analysed., Results: Circulating LEPC levels were significantly increased in SpA (p=0.0006) and SC (p=0.0058) patients compared with controls. In CD patients, LEPC counts negatively correlated with disease duration, with lower levels in longstanding disease (>20 years, p=0.018), but were not different from controls. No significant difference in VEGF-C levels was found in SpA, SC and CD compared with controls. Both LEPC and VEGF-C levels were independent of BASDAI and CDAI., Conclusions: On the basis of our observations, an active mobilisation of lymphatic endothelial cell precursors was observed only for spondylitis involvement.

K+ Channels form the largest family among ion channels. Besides regulating many physiological functions, K+ channels, being aberrantly expressed in different types of tumors, affect several hallmarks of cancer. In cancer cells, K+ channel activity regulates cell proliferation, resistance to apoptotic cell death, tumor angiogenesis, invasiveness and metastatic spread. Moreover, being expressed in cells of the tumor microenvironment, K+ channels can also modulate the immune/inflammatory response which contributes to drive cancer establishment and progression. After almost 30 years of studies, some K+ channels are emerging as novel cancer biomarkers, to be employed to stratify patients for either prognostic or predictive purposes. Moreover, it is not remote the time in which it will be possible to target specific K+ channels in cancer for therapeutic purposes. One hindrance for applying a K+ channel-based therapy to cancer is the fact that K+ channel blockers can cause side effects, which often overlap with, but can mask, benefits. We here show some strategies to overcome harmful side effects caused by blocking K+ channels. Once taken into account these strategies, K+ channels may represent suitable and easily accessible cancer biomarkers and targets for therapy. The relevant patents related to K+ channels and cancer are discussed.