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    • The molecular identity of KCC has

    2018-10-23

    The molecular identity of KCC has been established with four isoforms identified to date, of which three (KCC1, 3 and 4) are found in red HZ-1157 (Gillen et al., 1996; Pellegrino et al., 1998). In addition, splice variants do occur (Crable et al., 2005), which may be relevant to the different behaviour of KCC in red cells from HbSS and HbSC patients. Physiological regulation of KCC is also complex (Gibson and Ellory, 2003), with evidence for cascades of protein kinases and phosphatases (Cossins et al., 1994), acting on both serine–threonine and tyrosine residues, impacting on transporter activity. This enzymatic regulation is probably key to the differences in response to O2 (Gibson et al., 1994; Merciris et al., 2001), perhaps interacting with Hb at the level of the red cell membrane (Sega et al., 2012, 2015). This aspect, however, remains to be fully elucidated. Maintaining red cell hydration would reduce some of the complications of SCD through reducing the tendency for HbS to polymerise, and represents a longstanding clinical goal (eg Rosa et al., 1980). This is particularly so in red cells from HbSC patients, in which HbS comprises roughly only 50% of the total intracellular Hb. Hydration of these cells would require only a modest increase to reduce the tendency of HbS to polymerise (Fabry et al., 1982). Again, most work has been carried out on red cells from homozygous HbSS patients. To date, the most successful strategy has been identification of reagents which inhibit the Gardos channel. Clotrimazole (Ellory et al., 1992), the in vitro inhibitor employed in the current study, cannot be used clinically, as its imidazole ring appears to cause hepatopathy (Brugnara et al., 1996). Analogues such as ICA-17,043 (“senicapoc”) have progressed to clinical trials and were successful at increasing red cell hydration in SCD patients (Stocker et al., 2003; Ataga et al., 2008, 2011). Their use has been discontinued as they were unable to reduce pain episodes. Partial Psickle inhibitors also exist. They include anion exchange inhibitors such as the stilbenes (Joiner, 1990), but the use of such compounds is precluded by the wide distribution of these transporters through body tissues. Dipyridamole, which is used clinically as an anti-thrombotic compound, also partially reduces Psickle activity (Joiner et al., 2001), and has had some success at reducing clinical signs of SCD (Chaplin et al., 1980; Wun et al., 2013). No specific inhibitor of KCC has progressed to clinical trials, however, although compounds like H74 were shown to specifically target KCC over the related Na+-K+-2Cl− cotransporter (NKCC) (Ellory et al., 1990). This molecule, or its related analogues, represent compounds of promise. Simple Mg supplementation has also been used in limited clinical trials, as elevated red cell Mg inhibits KCC activity, with some success (De Franceschi et al., 1997; De Franceschi et al., 2000). If KCC activity is implicated as a key mechanism in pathogenesis, of particular importance in HbSC patients, re-evaluation of potential KCC inhibitors is warranted. An alternative approach has involved the development of compounds that directly interpolate with HbS molecules, to increase oxygen affinity and to reduce polymerisation upon deoxygenation. Aromatic aldehydes have shown promise and one of them, 5-hydroxymethyl-2-furfural (5HMF), is currently in phase II clinical trials in SCD patients in the US and UK (Abdulmalik et al., 2005; Stern et al., 2012; Health NIH, 2013; Safo and Kato, 2014). We have recently shown that it has additional effects on K+ transport, with inhibition of Psickle and Gardos channel and increased hydration, in red cells from SCD patients (Hannemann et al., 2014).
    Acknowledgements
    Authors\' Contributions
    Declaration of Interests
    Introduction Small cell lung cancer (SCLC) comprises approximately 15–18% of all lung cancers worldwide (Fruh et al., 2013). SCLC is the most aggressive subtype of lung cancer and is characterized by rapid doubling time, high growth fraction, and early widespread metastasis (Kalemkerian et al., 2013). Despite high response rates to initial treatment, SCLC usually relapses and becomes refractory to treatment within one year. The median survival is 14–20months for limited SCLC and 9–11months for extensive SCLC (Kalemkerian et al., 2013). These statistics highlight the need for new tools to aid in diagnosis and prevention.