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Balza E, Carlone S, Carta S, et al. Therapeutic efficacy of proton transport inhibitors alone or in combination with cisplatin in triple negative and hormone sensitive breast cancer models. Cancer Med. 2021;doi: 10.1002/cam4.4371.
Balza, E., Carlone, S., Carta, S., Piccioli, P., Cossu, V., Marini, C., Sambuceti, G., Rubartelli, A., & Castellani, P. (2021). Therapeutic efficacy of proton transport inhibitors alone or in combination with cisplatin in triple negative and hormone sensitive breast cancer models. Cancer medicine, . https://doi.org/10.1002/cam4.4371
Balza, Enrica, et al. "Therapeutic efficacy of proton transport inhibitors alone or in combination with cisplatin in triple negative and hormone sensitive breast cancer models." Cancer medicine vol. (2021). doi: https://doi.org/10.1002/cam4.4371
Balza E, Carlone S, Carta S, Piccioli P, Cossu V, Marini C, Sambuceti G, Rubartelli A, Castellani P. Therapeutic efficacy of proton transport inhibitors alone or in combination with cisplatin in triple negative and hormone sensitive breast cancer models. Cancer Med. 2021 Nov 18; doi: 10.1002/cam4.4371. Epub 2021 Nov 18. PMID: 34796694.
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Cancer Med. 2021 Nov 18; doi: 10.1002/cam4.4371. Epub 2021 Nov 18.

Therapeutic efficacy of proton transport inhibitors alone or in combination with cisplatin in triple negative and hormone sensitive breast cancer models.

Cancer medicine

Enrica Balza, Sebastiano Carlone, Sonia Carta, Patrizia Piccioli, Vanessa Cossu, Cecilia Marini, Gianmario Sambuceti, Anna Rubartelli, Patrizia Castellani

Affiliations

  1. Cell Biology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
  2. Nuclear Medicine, IRCCS Ospedale Policlinico San Martino, Genova, Italy.
  3. Department of Health Sciences, University of Genoa, Genoa, Italy.
  4. Bioimaging and Physiology (IBFM), CNR Institute of Molecular, Milan, Italy.
  5. Vita-Salute San Raffaele University, Milan, Italy.

PMID: 34796694 DOI: 10.1002/cam4.4371

Abstract

Triple negative breast cancers (TNBCs) are very aggressive and have a poor prognosis due to lack of efficacious therapies. The only effective treatment is chemotherapy that however is frequently hindered by the occurrence of drug resistance. We approached this problem in vitro and in vivo on a triple negative and a hormone sensitive breast cancer cell lines: 4T1 and TS/A. A main defense mechanism of tumors is the extrusion of intracellular protons derived from the metabolic shift to glycolysis, and necessary to maintain an intracellular pH compatible with life. The resulting acidic extracellular milieu bursts the malignant behavior of tumors and impairs chemotherapy. Therefore, we investigated the efficacy of combined therapies that associate cisplatin (Cis) with proton exchanger inhibitors, such as esomeprazole (ESO) and 5-(N-ethyl-N-isopropyl)amiloride (EIPA). Our results demonstrate that in the 4T1 triple negative model the combined therapy Cis plus EIPA is significantly more effective than the other treatments. Instead, in the TS/A tumor the best therapeutic result is obtained with ESO alone. Remarkably, in both 4T1 and TS/A tumors these treatments correlate with increase of CD8

© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Keywords: breast cancer; cisplatin; combo therapies; immune response; proton exchanger inhibitors

References

  1. Schettini F, Buono G, Cardalesi C, Desideri I, De Placido S, Del Mastro L. Hormone receptor/human epidermal growth factor receptor 2-positive breast cancer: where we are now and where we are going. Cancer Treat Rev. 2016;46:20-26. - PubMed
  2. Won K-A, Spruck C. Triple-negative breast cancer therapy: current and future perspectives. Int J Oncol. 2020;57:1245-1261. - PubMed
  3. Waks AG, Winer EP. Breast cancer treatment: a review. JAMA. 2019;321:288-300. - PubMed
  4. Martin HL, Smith L, Tomlinson DC. Multidrug-resistant breast cancer: current perspectives. Breast Cancer (Dove Med Press). 2014;6:1-13. - PubMed
  5. Marrocco I, Romaniello D, Yarden Y. Cancer immunotherapy: the dawn of antibody cocktails. Methods Mol Biol. 2019;1904:11-51. - PubMed
  6. Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014;740:364-378. - PubMed
  7. Balza E, Castellani P, Delfino L, Truini M, Rubartelli A. The pharmacologic inhibition of the xc- antioxidant system improves the antitumor efficacy of COX inhibitors in the in vivo model of 3-MCA tumorigenesis. Carcinogenesis. 2013;34:620-626. - PubMed
  8. Balza E, Castellani P, Sanchez-Moreno P, et al. Restoring microenvironmental redox and pH homeostasis inhibits neoplastic cell growth and migration: therapeutic efficacy of esomeprazole plus sulfasalazine on 3-MCA-induced sarcoma. Oncotarget. 2017;8:67482-67496. - PubMed
  9. Schwartz L, Seyfried T, Alfarouk KO, Da Veiga MJ, Fais S. Out of Warburg effect: an effective cancer treatment targeting the tumor specific metabolism and dysregulated pH. Semin Cancer Biol. 2017;43:134-138. - PubMed
  10. Zheng T, Jäättelä M, Liu B. pH gradient reversal fuels cancer progression. Int J Biochem Cell Biol. 2020;125:105796-105805. - PubMed
  11. De Simone G, Supuran CT. Carbonic anhydrase IX: biochemical and crystallographic characterization of a novel antitumor target. Biochim Biophys Acta. 2010;1804:404-409. - PubMed
  12. Forgac M. Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat Rev Mol Cell Biol. 2007;8:917-929. - PubMed
  13. Fliegel L. The Na+/H+ exchanger isoform 1. Int J Biochem Cell Biol. 2005;37:33-37. - PubMed
  14. Amith SR, Fliegel L. Na+/H+ exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics. Semin Cancer Biol. 2017;43:35-41. - PubMed
  15. Gerweck LE, Vijayappa S, Kozin S. Tumor pH controls the in vivo efficacy of weak acid and base chemotherapeutics. Mol Cancer Ther. 2006;5:1275-1279. - PubMed
  16. Fais S. Proton pump inhibitor-induced tumour cell death by inhibition of a detoxification mechanism. J Intern Med. 2010;2010(267):515-525. - PubMed
  17. Murakami T, Shibuya I, Ise T, et al. Elevated expression of vacuolar proton pump genes and cellular pH in cisplatin resistance. Int J Cancer. 2001;93:869-874. - PubMed
  18. Federici C, Petrucci F, Caimi S, et al. Exosome release and low pH belong to a framework of resistance of human melanoma cells to cisplatin. PLoS One. 2014;9:e88193-e88203. - PubMed
  19. Pillai SR, Damaghi M, Marunaka Y, Spugnini EP, Fais S, Gillies RJ. Causes, consequences, and therapy of tumors acidosis. Cancer Metastasis Rev. 2019;38(1-2):205-222. - PubMed
  20. Ramirez C, Hauser AD, Vucic EA, Bar-Sagi D. Plasma membrane V-ATPase controls oncogenic RAS-induced macropinocytosis. Nature. 2019;576:477-481. - PubMed
  21. Collins MP, Forgac M. Regulation and function of V-ATPases in physiology and disease. Biochim Biophys Acta Biomembr. 2020;12:183341-183353. - PubMed
  22. Luciani F, Spada M, De Milito A, et al. Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs. J Natl Cancer Inst. 2004;96:1702-1713. - PubMed
  23. Chen M, Lu J, Wei W, et al. Effects of proton pump inhibitors on reversing multidrug resistance via downregulating V-ATPases/PI3K/Akt/mTOR/HIF-1α signaling pathway through TSC1/2 complex and Rheb in human gastric adenocarcinoma cells in vitro and in vivo. Onco Targets Ther. 2018;11:6705-6722. - PubMed
  24. Wang BY, Zhang J, Wang JL, et al. Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer. J Exp Clin Cancer Res. 2015;34(1):85. - PubMed
  25. Lu ZN, Tian B, Guo XL. Repositioning of proton pump inhibitors in cancer therapy. Cancer Chemother Pharmacol. 2017;80(5):925-937. - PubMed
  26. Guan X, Hasan MN, Begum G, et al. Blockade of Na/H exchanger stimulates glioma tumor immunogenicity and enhances combinatorial TMZ and anti-PD-1 therapy. Cell Death Dis. 2018;9:1010. - PubMed
  27. Rojas EA, Corchete LA, San-Segundo L, et al. Amiloride, an old diuretic drug, is a potential therapeutic agent for multiple myeloma. Clin Cancer Res. 2017;23:6602-6615. - PubMed
  28. Chen Q, Liu Y, Zhu XL, Feng F, Yang H, Xu W. Increased NHE1 expression is targeted by specific inhibitor cariporide to sensitize resistant breast cancer cells to doxorubicin in vitro and in vivo. BMC Cancer. 2019;19:211-223. - PubMed
  29. Maidorn RP, Cragoe EJ Jr, Tannock IF. Therapeutic potential of analogues of amiloride: inhibition of the regulation of intracellular pH as a possible mechanism of tumour selective therapy. Br J Cancer. 1993;67:297-303. - PubMed
  30. Ferrari S, Perut F, Fagioli F, et al. Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients’ bed. J Transl Med. 2013;11:268-274. - PubMed
  31. Rebillard A, Tekpli X, Meurette O, et al. Cisplatin-induced apoptosis involves membrane fluidification via inhibition of NHE1 in human colon cancer cells. Cancer Res. 2007;67:7865-7874. - PubMed
  32. Amith SR, Wilkinson JM, Baksh S, Fliegel L. The Na+/H+ exchanger (NHE1) as a novel co-adjuvant target in paclitaxel therapy of triple-negative breast cancer cells. Oncotarget. 2015;6:1262-1275. - PubMed
  33. Nanni P, de Giovanni C, Lollini PL, Nicoletti G, Prodi G. TS/A: a new metastasizing cell line from a BALB/c spontaneous mammary adenocarcinoma. Clin Exp Metastasis. 1983;1:373-380. - PubMed
  34. De Milito A, Canese R, Marino ML, et al. pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. Int J Cancer. 2010;127:207-219. - PubMed
  35. Ceccarelli J, Delfino L, Zappia E, et al. The redox state of the lung cancer microenvironment depends on the levels of thioredoxin expressed by tumor cells and affects tumor progression and response to prooxidants. Int J Cancer. 2008;123:1770-1778. - PubMed
  36. Rowson-Hodel AR, Berg AL, Wald JH, et al. Hexamethylene amiloride engages a novel reactive oxygen species- and lysosome-dependent programmed necrotic mechanism to selectively target breast cancer cells. Cancer Lett. 2016;375:62-72. - PubMed
  37. Jia Y, Zhou D, Jia Q, Ying Y, Chen S. Synergistic and attenuated effect of HSS in combination treatment with docetaxel plus cisplatin in human non-small-cell lung SPC-A-1 tumor xenograft. Biomed Pharmacother. 2016;79:27-34. - PubMed
  38. Cha YJ, Koo JS. Role of tumor-associated myeloid cells in breast cancer. Cells. 2020;9:1785. - PubMed
  39. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3:401-410. - PubMed
  40. Pedersen SF. The Na+/H+ exchanger NHE1 in stress-induced signal transduction: implications for cell proliferation and cell death. Pflugers Arch. 2006;452:249-259. - PubMed
  41. Takakuwa S, Mizuno N, Takano T, et al. Down-regulation of Na+/H+ exchanger 1 by Toll-like receptor stimulation in macrophages. Immunobiology. 2017;222:176-182. - PubMed
  42. Cipriano DJ, Wang Y, Bond S, et al. Structure and regulation of the vacuolar ATPases. Biochim Biophys Acta. 2008;1777:599-604. - PubMed
  43. Colligan SH, Tzetzo SL, Abrams SI. Myeloid-driven mechanisms as barriers to antitumor CD8(+) T cell activity. Mol Immunol. 2020;118:165-173. - PubMed
  44. Parikh N, Howden CW. The safety of drugs used in acid-related disorders and functional gastrointestinal disorders. Gastroenterol Clin N Am. 2010;39:529-542. - PubMed
  45. Bardou M, Martin J, Barkun A. Intravenous proton pump inhibitors: an evidence-based review of their use in gastrointestinal disorders. Drugs. 2009;69:435-448. - PubMed
  46. Fais S. Evidence-based support for the use of proton pump inhibitors in cancer therapy. J Transl Med. 2015;13:368-372. - PubMed
  47. Blanchard A, Vargas-Poussou R, Vallet M, et al. Indomethacin, amiloride, or eplerenone for treating hypokalemia in gitelman syndrome. J Am Soc Nephrol. 2015;26:468-475. - PubMed
  48. Millar JA, Fraser R, Mason P, Leckie B, Cumming AM, Robertson JI. Metabolic effects of high dose amiloride and spironolactone: a comparative study in normal subjects. Br J Clin Pharmacol. 1984;18:369-375. - PubMed
  49. Butler D. Translational research: crossing the valley of death. Nature. 2008;453:840-842. - PubMed
  50. Pessetto ZY, Weir SJ, Sethi G, Broward MA, Godwin AK. Drug repurposing for gastrointestinal stromal tumor. Mol Cancer Ther. 2013;12:1299-1309. - PubMed

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