TY - JOUR
AU - Capasso,, Giovambattista
AB - Cisplatin is an old molecule and, as such, a successful, long-living drug; consider that aspirin was first synthesized around 1853 by Gerhardt, whereas cisplatin dates back to 1845 by Peyrone, both still used nowadays. While aspirin was introduced in clinical practice almost immediately, the clinical usefulness of cisplatin was delayed for about 100 years after its discovery when, in 1969, Barnett Rosenberg and Loretta VanCamp first reported its anti-tumoural efficacy in mice [1]. In the clinical setting, cisplatin is injected into the bloodstream where it is inactivated into a toxic compound upon binding to albumin and thioles; conversely, the remaining free form, once it has entered into the cells (an environment with low chloride ions), is acquired and hence binds to the DNA. The tumours with greater response to cisplatin-based treatments are lymphoma, carcinomas (e.g. hepatoblastoma) and sarcomas. However, other tumours are unaffected by cisplatin (e.g. colon cancer), whereas some gain resistance possibly through a higher expression of thioles (e.g. ovarian cancer). Finally, in non-small-cell lung cancer, cisplatin is not used as a single agent but as a combination. Despite its efficacy, the side effects of cisplatin are substantial, limiting its use. Hearing loss is frequent, and it is particularly debilitating in children. Furthermore, acute kidney injury is another major side effect, impacting patients' tolerability and outcomes. The first therapeutic approach proposed to limit cisplatin-nephrotoxicity was the forced diuresis using hypertonic saline or mannitol [2]. Diuresis induced by the atrial natriuretic factor was also tested in animal models [3]. Today, we know that the hydration/diuretic approach has limited benefits, but, at the same time, it remains the most useful intervention. Calcium blockers were then proposed in the 1980s although this option has been abandoned [4]. It is possible that some protective effect of this treatment was mediated by interference with parathyroid hormone [5]. Subsequently, it was observed that the drug accumulates in the S3 segment of the proximal tubule, with concomitant glutathione depletion and high levels of mitochondrial reactive oxygen species [6]. This may be related to cisplatin selective uptake via an active basolateral-to-apical transport due to the high-affinity copper transporter 1 (CTR1) and the organic cation transporter 2 (OCT2), both expressed on the basolateral membrane of the S3 segment. Indeed, OCT2 knockout animals showed in vivo reduced cisplatin nephrotoxicity [7]. Therefore, glutathione analogues (such as amifostine) and other free-oxygen radical scavengers such as α-tocopherol, vitamin C and N-acetylcysteine were suggested to prevent nephrotoxicity [8]. In the same direction, nucleophilic sulphur thiols, neurotrophins, phosphonic acid and melanocortins were proposed as possible nephroprotective treatments, again with unclear usefulness. Furthermore, these attempts to limit nephrotoxic effects were possibly limiting the anticancer effects of cisplatin [9]. Among these approaches, one molecule appears to have protective effects without causing changes in the anticancer ability of cisplatin: sodium thiosulphate (20 g/m2 intravenously in 15 min, 6 h after discontinuation of cisplatin) has been recently found to reduce the incidence of hearing loss by 48% [10]. Unfortunately, this protective effect is limited to hearing loss, without a nephroprotective ability. In the 2000s the focus shifted onto the mitogen-activated protein kinase (MAPK) pathway and gene regulation [9]. The nephrotoxic and ototoxic effects of cisplatin were found to involve apoptosis and necrosis in a dose-dependent manner [11]. In the kidney, almost all cell types are affected by cisplatin: glomeruli, tubules and blood vessels [9]. Many toxicity-related pathways have been described: cyclins, MAPK, p53, inflammation and oxidative stress [12]. The toxic effects of cisplatin are, unfortunately, irreversible upon suspension of the drug [13]. In summary, the approaches based on the in-depth knowledge of the damage mechanisms after cisplatin did not result in major therapeutic advances, apart from the promising use of sodium thiosulphate to prevent ototoxicity. The paper by Iwakura et al. in this issue of Nephrology Dialysis Transplantation [14] proposes the use of a new type of antidiabetic, called dipeptidyl peptidase-4 inhibitors (DPP-4i), to prevent cisplatin nephrotoxicity. The transmembrane enzyme DPP-4 has been under the scope of diabetologists since the 1990s, because it degrades a group of peptidic hormones called ‘incretins’, known to regulate blood glucose [15]. Thanks to these studies we have today a new class of oral antidiabetics, the DPP-4i, such as saxagliptin, linagliptin, teneligliptin, etc. However, DPP-4 has been studied since the 1980s by immunologists: on one hand, T-lymphocytes were known to have DPP-4 activity on their surface [16]; on the other hand, T-lymphocytes were classified by a surface marker (CD26) in the second workshop for Human Leukocyte Differentiation Antigen held in Boston in 1984 [17]. Later on, studies found that CD26 and DPP-4 were the same molecule [18]. Since CD26/DPP-4 was also known to activate T-lymphocytes, in 2006, Zhai et al. tested if its blockade could improve the ischaemia–reperfusion damage of transplanted lungs [19], according to the hypothesis that this damage is modulated by T-cells. The encouraging effect was then confirmed by other groups, and later tested also on ischaemia-reperfusion damage from myocardial infarction [20]. Therefore, in 2012, Glorie et al. tested DPP-4 inhibition also on ischaemia–reperfusion damage in kidney after transplantation, with promising results [21]. These data almost immediately led to the hypothesis that the DPP-4i could actually exert nephroprotective effects also in other types of kidney damage, even outside the realm of diabetes and transplantation. Thus, Katagiri et al. verified that DPP-4i actually protects the kidney also in the case of renal injury caused by cisplatin [22]. They not only confirmed the protective effects in this rather different situation, but ascribed the effects to the reduced degradation of an incretin, glucagon-like peptide-1 (GLP-1). In 2014, Nistala et al. found nephroprotective effects also in obese, non-diabetic rats [23]. Tanaka et al. demonstrated nephroprotective effects of DPP-4i in mice with tubulointerstitial injury induced by intraperitoneal injection of free fatty acids (FFA) bound to albumin [24]. Tsuprykov et al. showed that DPP-4i protected the kidney also in an animal model of chronic kidney disease (CKD), the 5/6 nephrectomy [25]. These authors further demonstrated in knock-out animals that this effect was mediated by DPP-4 and suggested that GLP-1 or glycaemia did not mediate this effect. Finally, Uchida et al. reported protective effects of DPP-4i after unilateral ureteral obstruction, leading to progressive renal fibrosis [26]. Given the protective role of DPP-4i in ischaemia–reperfusion and in cisplatin damage, the mechanism-of-action of DPP-4i in this scenario remains unclear. DPP-4 is an enzyme expressed on several cell types, primarily T-lymphocytes, smooth muscle cells, salivary glands and, to a lesser extent, in other organs, including the kidney (data from BioGPS database; Figure 1). Within the kidney, it is expressed in glomerular cells (epithelia and endothelium) and proximal tubule cells [27]. Furthermore, its proteolytic activity is also not specific for incretins: chemokines, haematopoietic growth factors and neuropeptides can be degraded as well [27]. Therefore, it is possible that the nephroprotective effects of DPP-4 are not linked to its anti-diabetic action or its action on T-cells, and that incretins are not mediating these ‘side effects’. FIGURE 1 Open in new tabDownload slide Interaction between DPP-4i and cisplatin-induced nephrotoxicity. DPP-4i are used as antidiabetic drugs due to their effects on incretins [GLP-1/glucose-dependent insulinotropic polypeptide (GIP)], which regulate glycaemia. However, the enzyme DPP-4 is expressed on many cell types and modulates many other compounds (chemokines, etc). The net effect of DPP-4 inhibition on the kidney is the modulation of cell repair of PTECs, thus contrasting the nephrotoxic effects of cisplatin and other Noxa. FIGURE 1 Open in new tabDownload slide Interaction between DPP-4i and cisplatin-induced nephrotoxicity. DPP-4i are used as antidiabetic drugs due to their effects on incretins [GLP-1/glucose-dependent insulinotropic polypeptide (GIP)], which regulate glycaemia. However, the enzyme DPP-4 is expressed on many cell types and modulates many other compounds (chemokines, etc). The net effect of DPP-4 inhibition on the kidney is the modulation of cell repair of PTECs, thus contrasting the nephrotoxic effects of cisplatin and other Noxa. Overall, since DPP-4i appear beneficial in very different kidney insults (cisplatin, ischemia–reperfusion, ureteral obstruction, tubule damage by FFA or obesity, subtotal nephrectomy), it is unlikely that they act by interfering with the pathogenesis of the damage itself. Indeed, the paper by Iwakura et al. [14] suggests that DPP-4i may work downstream any type of kidney damage, by modulating the repairing events: (i) by reducing the intrarenal inflammation consequent to the damage; and (ii) by inducing the proliferation of proximal tubular epithelial cells (PTECs), which is required to repair the damage (Figure 1). Iwakura et al. find that teneligliptin inhibits the breakdown of C-X-C motif chemokine 12 (CXCL12), a mitogenic factor, thus promoting the proliferation of surviving epithelial cells of PTEC after damage. Furthermore, it provides an anti-inflammatory effect through suppression of intrarenal tumor necrosis factor alpha (TNF-α), and macrophage anti-inflammatory M2 phenotype. The consequent greater proliferation and lesser inflammatory damage are expected to limit nephrotoxicity. These intriguing results certainly are consistent with the variety of situations where DPP-4i has demonstrated nephroprotective action, apart from the cisplatin damage. However, these data also raise new questions. First of all, DPP-4i are currently largely used to treat patients with diabetes; however, no kidney side effects have been noted at present in patients treated with DPP4i. The data reported by Iwakura et al. suggest that a detailed analysis of urine composition in these patients may reveal some modification of renal function after DPP-4i treatment. Secondly, current studies have not tested the effects of DPP-4i on the anticancer action of cisplatin. This, of course, should be verified before DPP-4i can be used to prevent cisplatin-induced nephrotoxicity. Finally, this new field opens the possibility that these compounds are also active in other types of kidney damage, such as contrast-induced nephropathy. CONFLICT OF INTEREST STATEMENT None declared. (See related article by Iwakura et al. 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TI - A quest for protecting kidneys from cisplatin toxicity
JO - Nephrology Dialysis Transplantation
DO - 10.1093/ndt/gfz029
DA - 2019-10-01
UR - https://www.deepdyve.com/lp/oxford-university-press/a-quest-for-protecting-kidneys-from-cisplatin-toxicity-CG9ATDxLq0
SP - 1623
VL - 34
IS - 10
DP - DeepDyve
ER -