Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015, 159(4):519-526 | DOI: 10.5507/bp.2015.060

A minireview on NHE1 inhibitors. A rediscovered hope in oncohematology

Romeo Gabriel Mihaila
Faculty of Medicine, "Lucian Blaga" University of Sibiu and Department of Hematology, Emergency County Clinical Hospital Sibiu, Romania

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.

Keywords: amiloride, apoptosis, BCR/ABL, cariporide, FLT3/ITD, heme oxygenase-1, leukemia, Na+/H+ exchanger, imatinib mesylate, intracellular pH, isoprenylation, leukemia, lovastatin, P-glycoprotein, sorafenib, statins

Received: September 13, 2015; Accepted: November 23, 2015; Prepublished online: November 27, 2015; Published: December 3, 2015  Show citation

ACS AIP APA ASA Harvard Chicago IEEE ISO690 MLA NLM Turabian Vancouver
Mihaila, R.G. (2015). A minireview on NHE1 inhibitors. A rediscovered hope in oncohematology. Biomedical papers, 159(4), 519-526. doi: 10.5507/bp.2015.060
Share...
Download citation
  • BibTeX (.bib)
  • Bookends (.ris)
  • EasyBib (.ris)
  • EndNote (.enw)
  • EndNote 8 (.xml)
  • ISI WoS (.isi)
  • Medlars (.medlars)
  • Mendeley (.ris)
  • MODS (.xml)
  • Papers (.ris)
  • RefWorks (.txt)
  • RefManager (.ris)
  • RIS (.ris)
  • MS Word (.xml)
  • Zotero (.ris)
    • Open full article

    References

    1. Hrgovic I, Glavic Z, Kovacic Z, Mulic S, Zunic L, Hrgovic Z. Repeated administration of inhibitors for ion pumps reduce markedly tumor growth in vivo. Med Arch 2014;68(2):76-8. Go to original source... Go to PubMed...
    2. Spugnini EP, Sonveaux P, Stock C, Perez-Sayans M, De Milito A, Avnet S, Garcìa AG, Harguindey S, Fais S. Proton channels and exchangers in cancer. Biochim Biophys Acta 2014;1848(10 Pt B):2715-26. Go to original source... Go to PubMed...
    3. Daniel C, Bell C, Burton C, Harguindey S, Reshkin SJ, Rauch C. The role of proton dynamics in the development and maintenance of multidrug resistance in cancer. Biochim Biophys Acta 2013;1832(5):606-17. Go to original source... Go to PubMed...
    4. Rich IN, Worthington-White D, Garden OA, Musk P. Apoptosis of leukemic cells accompanies reduction in intracellular pH after targeted inhibition of the Na(+)/H(+) exchanger. Blood 2000;95(4):1427-34. Go to original source...
    5. Malo ME, Fliegel L. Physiological role and regulation of the Na+/H+ exchanger. Can J Physiol Pharmacol 2006 Nov;84(11):1081-95. Go to original source... Go to PubMed...
    6. Reshkin SJ, Cardone RA, Harguindey S. Na+-H+ exchanger, pH regulation and cancer. Recent Pat Anticancer Drug Discov 2013;8(1):85-99. Go to original source... Go to PubMed...
    7. Harguindey S, Arranz JL, Polo Orozco JD, Rauch C, Fais S, Cardone RA, Reshkin SJ. Cariporide and other new and powerful NHE1 inhibitors as potentially selective anticancer drugs--an integral molecular/biochemical/metabolic/clinical approach after one hundred years of cancer research. J Transl Med 2013;11:282. Go to original source... Go to PubMed...
    8. Reshkin SJ, Bellizzi A, Caldeira S, Albarani V, Malanchi I, Poignee M, Alunni-Fabbroni M, Casavola V, Tommasino M. Na+/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes. FASEB 2000;14(14):2185-97. Go to original source... Go to PubMed...
    9. Mirossay A, Mirossay L, Sarisský M, Papp P, Mojzis J. Modulation of the phototoxic effect of hypericin in human leukemia CEM cell line by N-ethylmaleimide, amiloride and omeprazole. Physiol Res 2002;51(6):641-4.
    10. Mirossay L, Mirossay A, Kocisová E, Radváková I, Miskovský P, Mojzis J. Hypericin-induced phototoxicity of human leukemic cell line HL-60 is potentiated by omeprazole, an inhibitor of H+K+-ATPase and 5'-(N,N-dimethyl)-amiloride, an inhibitor of Na+/H+ exchanger. Physiol Res 1999;48(2):135-41.
    11. Man CH, Lam SS, Sun MK, Chow HC, Gill H, Kwong YL, Leung AY. A novel tescalcin-sodium/hydrogen exchange axis underlying sorafenib resistance in FLT3-ITD+ AML. Blood 2014;123(16):2530-9. Go to original source... Go to PubMed...
    12. Jin W, Li Q, Lin Y, Lu Y, Li H, Wang L, Hu R, Ma L, Wang J, Pang T. Reversal of Imatinib resistance in BCR-ABL-positive leukemia after inhibition of the Na+/H+ exchanger. Cancer Lett 2011;308(1):81-90. Go to original source... Go to PubMed...
    13. Affar el B, Shah RG, Dallaire AK, Castonguay V, Shah GM. Role of poly(ADP-ribose) polymerase in rapid intracellular acidification induced by alkylating DNA damage. Proc Natl Acad Sci U S A 2002;99(1):245-50. Go to original source... Go to PubMed...
    14. Wang J, Xu H, Zhang H, Wang Q, Wang C, Zhang H, Lin Y, Ru Y, Liang H, Li Q1, Pang T. CIAPIN1 targets Na+/H+ exchanger 1 to mediate K562 chronic myeloid leukemia cells' differentiation via ERK1/2 signaling pathway. Leuk Res 2014;38(9):1117-25. Go to original source... Go to PubMed...
    15. Mebratu Y, Tesfaigzi Y. How ERK1/2 activation controls cell proliferation and cell death: Is subcellular localization the answer? Cell Cycle 2009;8(8):1168-75. Go to original source... Go to PubMed...
    16. Shin S, Dimitri CA, Yoon SO, Dowdle W, Blenis J. ERK2, but not ERK1, induces epithelial to mesenchymal transformation via DEF motif dependent signaling events. Mol Cell 2010;38(1):114-27. Go to original source... Go to PubMed...
    17. Garden OA, Musk P, Worthington-White DA, Dewey MJ, Rich IN. Silent polymorphisms within the coding region of human sodium/hydrogen exchanger isoform-1 cDNA in peripheral blood mononuclear cells of leukemia patients: A comparison with healthy controls. Cancer Genet Cytogenet 2000;120(1):37-43. Go to original source... Go to PubMed...
    18. Hallows KR, Restrepo D, Knauf PA. Control of intracellular pH during regulatory volume decrease in HL-60 cells. Am J Physiol 1994;267(4 Pt 1):C1057-66. Go to original source... Go to PubMed...
    19. Jin W, Li Q, Wang J, Chang G, Lin Y, Li H, Wang L, Gao W, Pang T. Na+/H+ exchanger 1 inhibition contributes to K562 leukaemic cell differentiation. Cell Biol Int 2012;36(8):739-45. Go to original source... Go to PubMed...
    20. Jin WN, Wang J, Chang GQ, Lin YN, Wang LH, Li HW, Gao W, Li QH, Pang TX. Inhibition of NHE1 promotes hypoxia-induced differentiation of K562 leukemic cells. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2011;19(3):661-5. Go to PubMed...
    21. Zhao R, Oxley D, Smith TS, Follows GA, Green AR, Alexander DR. DNA damage-induced Bcl-xL deamidation is mediated by NHE-1 antiport regulated intracellular pH. PLoS Biol 2007;5(1):e1. Go to original source... Go to PubMed...
    22. Zhao R, Follows GA, Beer PA, Scott LM, Huntly BJ, Green AR, Alexander DR. Inhibition of the Bcl-xL deamidation pathway in myeloproliferative disorders. Engl J Med 2008;359(26):2778-89. Go to original source... Go to PubMed...
    23. Rich IN, Worthington-White D, Garden OA, Musk P. Apoptosis of leukemic cells accompanies reduction in intracellular pH after targeted inhibition of the Na(+)/H(+) exchanger. Blood 2000;95(4):1427-34. Go to original source...
    24. Masereel B, Pochet L, Laeckmann D. An overview of inhibitors of Na(+)/H(+) exchanger. European Journal of Medicinal Chemistry 2003;38(6):547-54. Go to original source... Go to PubMed...
    25. Chang WH, Liu TC, Yang WK, Lee CC, Lin YH, Chen TY, Chang JG. Amiloride modulates alternative splicing in leukemic cells and resensitizes Bcr-AblT315I mutant cells to imatinib. Cancer Res 2011;71(2):383-92. Go to original source... Go to PubMed...
    26. Gao W, Zhang H, Chang G, Xie Z, Wang H, Ma L, Han Z, Li Q, Pang T. Decreased intracellular pH induced by cariporide differentially contributes to human umbilical cord-derived mesenchymal stem cells differentiation. Cell Physiol Biochem 2014;33(1):185-94. Go to original source... Go to PubMed...
    27. Li H, Chang G, Wang J, Wang L, Jin W, Lin Y, Yan Y, Wang R, Gao W, Ma L, Li Q, Pang T. Cariporide sensitizes leukemic cells to tumor necrosis factor related apoptosis-inducing ligand by up-regulation of death receptor 5 via endoplasmic reticulum stress-CCAAT/enhancer binding protein homologous protein dependent mechanism. Leuk Lymphoma 2014;55(9):2135-40. Go to original source... Go to PubMed...
    28. Gao W, Chang G, Wang J, Jin W, Wang L, Lin Y, Li H, Ma L, Li Q, Pang T. Inhibition of K562 leukemia angiogenesis and growth by selective Na+/H+ exchanger inhibitor cariporide through down-regulation of pro-angiogenesis factor VEGF. Leuk Res 2011;35(11):1506-11. Go to original source... Go to PubMed...
    29. Pérez-Sala D, Collado-Escobar D, Mollinedo F. Intracellular alkalinization suppresses lovastatin-induced apoptosis in HL-60 cells through the inactivation of a pH-dependent endonuclease. J Biol Chem 1995;270(11):6235-42. Go to original source... Go to PubMed...
    30. Clark SS, Perman SM, Sahin MB, Jenkins GJ, Elegbede JA. Antileukemia activity of perillyl alcohol (POH): uncoupling apoptosis from G0/G1 arrest suggests that the primary effect of POH on Bcr/Abl-transformed cells is to induce growth arrest. Leukemia 2002;16(2):213-22. Go to original source... Go to PubMed...
    31. Alvarado Y, Kantarjian HM, Luthra R, Ravandi F, Borthakur G, Garcia-Manero G, Konopleva M, Estrov Z, Andreeff M, Cortes JE. Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations. Cancer 2014;120(14):2142-9. Go to original source... Go to PubMed...
    32. Ma D, Fang Q, Wang P, Gao R, Wu W, Lu T, Cao L, Hu X, Wang J. Induction of heme oxygenase-1 by Na+-H+ exchanger 1 protein plays a crucial role in imatinib-resistant chronic myeloid leukemia cells. Biol Chem 2015;290(20):12558-71. Go to original source... Go to PubMed...
    33. Hu RH, Jin WN, Chang GQ, Lin YN, Wang J, Ru YX, Li QH, Pang TX. Increasing sensitivity of leukemia cells to imatinib by inhibiting NHE1 and p38MAPK signaling pathway. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2012;20(6):1341-5. Go to PubMed...
    34. Li QH, Lu Y, Jin WN, Lin YN, Hu RH, Zhu XF, Wang JX, Pang TX. Effect of intracellular acidification on drug resistance of leukemia cells with high P-glycoprotein expression. Zhonghua Xue Ye Xue Za Zhi 2009;30(9):605-9. Go to PubMed...
    35. Sih HJ, Stolen C, Ou J, Wagner DO. Methods to position therapeutic agents using a magnetic field. US 20080006281 (2008).
    36. Wishart N, Argiriadi MA, Calderwood DJ, Ericsson AM, Fiamengo BA, Frank KE, Friedman MM, George DM, Goedken ER, Josephsohn NS, Li BC, Stewart KD, Wallace GA, Wang L, Woller KR. Tricyclic compounds. US 20090312338 (2009).
    37. Wishart N, Frank KE, Friedman M, George DM, Stewart KD, Wallace GA. Tricyclic compounds. US 20110311474 (2011).
    38. Watterson DM, Van Eldik LJ. Protein kinase targeted therapeutics. US 20110166153 (2011).
    39. Ghayur T, Salfeld JG, McPherson MJ. Dual variable domain immunoglobulins and uses thereof. US 20120087858 (2012).
    40. Rogers RD, Daly DT, Swatloski RP, Hough-Troutman WL, Davis Jr. JH, Smiglak M, Pernak J, Spear SK. Multi-functional ionic liquid compositions for overcoming polymorphism and imparting improved properties for active pharmaceutical, biological, nutritional, and energetic ingredients. US 20120264605 (2012).
    41. Wan MM, Avgerinos G, Zarbis-Papastoitsi G. Purified antibody composition. US 20130273059 (2013).
    42. Meyer MD, Wang X, Guo T, Wei RGP, Wang LJ. Chemokine receptor antagonists. US 20130261129 (2013).
    43. Neely LA, Audeh MJ, Blanco M, Chepin JF, Demas V, Dhanda RK, Lowery Jr. TJ. NMR systems and methods for the rapid detection of analytes. US 20130266944 (2013).

    Return to the content