title: 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.
  
  
  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.
authors.affiliation: Faculty of Medicine, "Lucian Blaga" University of Sibiu and Department of Hematology, Emergency County Clinical Hospital Sibiu, Romania.
authors.forename: Romeo Gabriel
authors.initials: RG
authors.lastname: Mihaila
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000502:physiology; D004347:Drug Interactions; D016313:Genes, abl / Q000235:genetics; D006146:Guanidines / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics; D000068877:Imatinib Mesylate / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D009994:Osmolar Concentration; D010330:Patents as Topic; D010671:Phenylurea Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000502:physiology; D000077157:Sorafenib; D013450:Sulfones / Q000494:pharmacology; D000072258:Tumor Hypoxia / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D006146:Guanidines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D009536:Niacinamide; D000584:Amiloride; C093373:cariporide; D000068877:Imatinib Mesylate; D000077157:Sorafenib; D051547:Heme Oxygenase-1; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: BCR/ABL; FLT3/ITD; Na+/H+ exchanger; P-glycoprotein; amiloride; apoptosis; cariporide; heme oxygenase-1; imatinib mesylate; intracellular pH; isoprenylation; leukemia; lovastatin; sorafenib; statins