A minireview on NHE1 inhibitors. A rediscovered hope in oncohematology

Abstract

Background. Na+ /H + exchanger-1 (NHE-1) is involved in pH regulation and is up-regulated in different malignancies. Activation of NHE-1 is one way for allowing cells to avoid intracellular acidification and protect them against apoptosis. Inhibitors of NHE-1 are able to decrease intracellular pH and induce apoptosis. Some statins can also act by partial inhibition of NHE-1. This review presents progress in understanding the mechanisms of action of these inhibitors, connections with certain genetic mutations and acquired treatment resistance, as well as new patents on them. Methods. A MEDLINE search for original and review articles using key terms, Na + /H + exchanger, leukemia, cariporide, and amiloride. Recent patents with NHE-1 inhibitors published by United States Patent and Trademark Office are also presented. Results and Conclusions. Sorafenib is used for the treatment of acute myeloid leukemia patients carrying internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) mutation. 5-(N, N-hexamethylene)-amiloride can increase the suppression of FLT3 signaling by sorafenib. NHE-1 inhibitors are able to increase the sensitivity of chronic myeloid leukemia cells to tyrosine kinase inhibitors, including through the inhibition of P-glycoprotein. NHE-1 inhibitors are promising adjuvant drugs for overcoming acquired resistance to treatment in various malignant hemopathies.

Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era

“…NHE1 levels are higher in BC tissue than in normal breast tissue, and also in resistant BC cells than in sensitive cells, in a similar fashion to other PTs [ 4 , 10 , 51 , 55 , 56 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ]. Apart from NHE1 overexpression, carbonic anhydrases also have an important role in the pathogenesis of BC, like V-ATPase proton pumps, the Na + –HCO 3 − cotransporter (SLC4A7,NBCn1, MCTs, hypoxia and hypoxia-inducing factor 1 (HIF-1) [ 75 ].…”

“…Since extracellular acidification also increases the activity of P-gp, in this way inducing MDR in different cancer cells and tissues [ 125 , 128 , 132 ], it becomes logical to associate PPI with PTI, not only to improve the effect of chemotherapy in metastatic BC, but also to overcome MDR. The clinical use of such a combination is considered a fundamental therapeutic measure in any integrated clinical protocol in the treatment of BC [ 4 , 10 , 30 , 31 , 64 , 67 , 68 , 71 , 72 , 73 , 78 , 101 , 122 , 124 , 139 , 140 , 165 , 167 , 174 , 175 , 180 , 188 , 189 , 190 , 195 , 196 , 197 , 202 , 208 , 233 , 307 , 308 , 309 , 310 , 311 ]. The integral pH-related approach to MDR has shown that the therapeutic failure in inducing the acidification of the cytoplasm and/or reverse CPR is the main factor underlying MDR.…”

Effect of cariporide on ram sperm pH regulation and motility: possible role of NHE1

“…Moreover, the in silico evidence that the human NHE1 protein has a remarkably different protein sequence and organization compared to sNHE suggested that both cariporide and DMA may be inactive on that isoform, for which published inhibition studies are still missing. The observed difference in the NHE1 inhibition of intracellular pH regulation between the two drugs adopted in the present study likely reflects their chemical nature (Mihaila 2015). Indeed, cariporide has been previously demonstrated to be a more potent, specific and selective inhibitor of NHE1 than other NHE inhibitors of the amiloride class (Siyanov & Baltz 2013).…”

“…In light of these considerations, and given the recent increased attention to NHE1-specific inhibitors, due to their use in the regulation of different cell functions with therapeutic purposes (Mihaila 2015), the aim of this study was to perform, for the first time, an evaluation of the effects of cariporide (HOE642), a documented selective inhibitor of NHE1, on sperm intracellular pH, motility and fertilizing ability. The study was performed on the ovine species as previous evidences supported it as an optimal animal model for translational studies in human reproductive physiology (Sutovsky et al 1996).…”

A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer based upon its Hydrogen Ion Dynamics

“…d) pH, proton transporters (PTs), proton pumps (PPs) and their inhibitors (PTIs and PPIs) [14,32,36,38,[41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]. e) pH and voltage gated sodium channels (VGSC) [56][57][58][59][60][61].…”