Skip to main content

Advertisement

SpringerLink
Log in

Comparative randomized trial evaluating the effect of proton pump inhibitor versus histamine 2 receptor antagonist as an adjuvant therapy in diffuse large B-cell lymphoma

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

The development of drug resistance remains the major obstacle to clinical efficacy of cancer chemotherapy. Consequently, finding new therapeutic options for cancerous patients is an urgent need. Sixty newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients were recruited from Clinical Oncology Department, Faculty of Medicine, Menoufia University, Egypt prospectively randomized to three groups (n = 20 for each group). Group one (control group) received R-CHOP standard chemotherapy {Rituximab, Cyclophosphamide, Hydroxyldaunorubicin (Doxorubicin)®, Vincristine (oncovin)®, prednisolone in the first five days of cycle}, group two received lansoprazole (LAN) 60 mg p.o. bid for only one week before starting each of cycle + R-CHOP and group three received famotidine (FAM) 40 mg p.o. once daily one week before cycle and continues daily through the cycle + R-CHOP for six cycles. Blood samples were obtained for biochemical analysis of transforming growth factor-β (TGF-β), Basic fibroblast growth factor (bFGF), interleukin-9 (IL-9), nuclear factor-kappa B (NF-κB) and Caspase 3 before and after six cycles of therapy. The obtained data showed that LAN and FAM resulted in significant decrease in (LDH, TGF-β, bFGF and IL-9, respectively) and significant increase in (Caspase-3). In addition, LAN produced a significant elevation in the response rate compared to the control group or the FAM group. Both LAN and FAM as adjuvant therapy represents a promising anticancer strategy in DLBCL by modulation of malignancy homeostasis mechanisms and boosting chemotherapy antitumor effects without further toxicity. In addition, LAN has a synergetic effect in improving the response rate.

Trial registration Clinical Trial.gov Identifier: NCT0364707.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

All data and materials are transparent as well as support published claims and comply with field standards transparency.

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics 2019. CA Cancer J Clin. 2019;69:7–34. https://doi.org/10.3322/caac.21551.

    Article  PubMed  Google Scholar 

  2. Cowgill KD, Loffredo CA, Eissa SA, Mokhtar N, Abdel-Hamid M, Fahmy A, et al. Case-control study of non-Hodgkin’s lymphoma and hepatitis C virus infection in Egypt. Int J Epidemiol. 2004;33:1034–9. https://doi.org/10.1093/ije/dyh183.

    Article  PubMed  Google Scholar 

  3. Jurisić V, Plećić M, Colović N, Čemerikić-Martinović V, Janković M, Čolović M. MUM-1 and bcl-2 Positive Primary Diffuse Large B Cell Non-Hodgkin’s Lymphoma of the Colon. Arch Iran Med. 2016;19:297–9.

    PubMed  Google Scholar 

  4. Coiffier B, Sarkozy C. Diffuse large B cell lymphoma: R-CHOP failure-what to do? Hematology Am Soc Hematol Educ Program. 2016;2016:366–78. https://doi.org/10.1182/asheducation-2016.1.366.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Jurišić V, Vuletić A, Martinović K, Konjević G. The role of NK cells in cancer. In: Rezaei N, editor. Cancer immunology. Cham: Springer; 2020. https://doi.org/10.1007/978-3-030-30845-2_9.

    Chapter  Google Scholar 

  6. Reslan L, Dalle S, Dumontet C. Understanding and circumventing resistance to anticancer monoclonal antibodies. mAbs. 2009;1:222–9. https://doi.org/10.4161/mabs.1.3.8292.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Jiang J, Liu Y, Tang Y, Li L, Zeng R, Zeng S, Zhong M. ALDH1A1 induces resistance to CHOP in diffuse large B cell lymphoma through activation of the JAK2/STAT3 pathway. Onco Targets Ther. 2016;9:5349–60. https://doi.org/10.2147/OTT.S107957.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP, Vikas P. The repurposing drugs in oncology (ReDO) project. Ecancermedicalscience. 2014;8:442. https://doi.org/10.3332/ecancer.2014.442.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Huber V, Camisaschi C, Berzi A, Ferro S, Lugini L, Triulzi T, et al. Cancer acidity: an ultimate frontier of tumor immune escape and a novel target of immunomodulation. Semin Cancer Biol. 2017;43:74–89. https://doi.org/10.1016/j.semcancer.2017.03.001.

    Article  PubMed  CAS  Google Scholar 

  10. Stransky L, Cotter K, Forgac M. The function of V-ATPases in cancer. Physiol Rev. 2016;96:1071–91. https://doi.org/10.1152/physrev.00035.2015.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Fais S. Evidence-based support for the use of proton pump inhibitors in cancer therapy. J Transl Med. 2015;13:368. https://doi.org/10.1186/s12967-015-0735-2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Ikemura K, Hiramatsu S, Okuda M. Drug repositioning of proton pump inhibitors for enhanced efficacy and safety of cancer chemotherapy. Front Pharmacol. 2017;8:911. https://doi.org/10.3389/fphar.2017.00911.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Wang BY, Zhang J, Wang JL, Sun S, Wang ZH, Wang LP, et al. Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer. J Exp Clin Cancer Res. 2015;34:2–12. https://doi.org/10.1186/s13046-015-0194-x.

    Article  CAS  Google Scholar 

  14. Marchetti P, Milano A, D’Antonio C, Romiti A, Falcone R, Roberto M, et al. Association between proton pump inhibitors and metronomic capecitabine as salvage treatment for patients with advanced gastrointestinal tumors: a Randomized Phase II Trial. Clin Colorectal Cancer. 2016;15:377–80. https://doi.org/10.1016/j.clcc.2016.06.005.

    Article  PubMed  Google Scholar 

  15. Shim YK, Kim N. The effect of H2 receptor antagonist in acid inhibition and its clinical efficacy. Korean J Gastroenterol. 2017;70:4–12. https://doi.org/10.4166/kjg.2017.70.1.4.

    Article  PubMed  Google Scholar 

  16. Faustino-Rocha AI, Ferreira R, Gama A, Oliveira PA, Ginja M. Antihistamines as promising drugs in cancer therapy. Life Sci. 2017;172:27–41. https://doi.org/10.1016/j.lfs.2016.12.008.

    Article  PubMed  CAS  Google Scholar 

  17. Vila-Leahey A, Oldford SA, Marignani PA, Wang J, Haidl ID, Marshall JS. Ranitidine modifies myeloid cell populations and inhibits breast tumor development and spread in mice. Oncoimmunology. 2016;5:e1151591. https://doi.org/10.1080/2162402X.2016.1151591.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Abdul-Hussein M, Freeman J, Castell D. Concomitant administration of a histamine 2 receptor antagonist and proton pump inhibitor enhances gastric acid suppression. Pharmacotherapy. 2015;35:1124–9. https://doi.org/10.1002/phar.1665.

    Article  PubMed  CAS  Google Scholar 

  19. Zhang S, Wang Y, Li SJ. Lansoprazole induces apoptosis of breast cancer cells through inhibition of intracellular proton extrusion. Biochem Biophys Res Commun. 2014;448:424–9. https://doi.org/10.1016/j.bbrc.2014.04.127.

    Article  PubMed  CAS  Google Scholar 

  20. Luciani F, Spada M, De Milito A, Molinari A, Rivoltini L, Montinaro A, et al. Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs. J Natl Cancer Inst. 2004;96:1702–13. https://doi.org/10.1093/jnci/djh305.

    Article  PubMed  CAS  Google Scholar 

  21. De Milito A, Canese R, Marino ML, Borghi M, Iero M, Villa A, et al. pH dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. Int J Cancer. 2010;127:207–19. https://doi.org/10.1002/ijc.25009.

    Article  PubMed  CAS  Google Scholar 

  22. Cataldi M, Borriello F, Granata F, Annunziato L, Marone G. Histamine receptors and antihistamines: from discovery to clinical applications. Chem Immunol Allergy. 2014;100:214–26. https://doi.org/10.1159/000358740.

    Article  PubMed  Google Scholar 

  23. Parshad R, Kapoor S, Gupta SD, Kumar A, Chattopadhyaya TK. Does famotidine enhance tumor infiltrating lymphocytes in breast cancer? Results of a randomized prospective pilot study. Acta Oncol. 2002;41:362–5. https://doi.org/10.1080/028418602760169415.

    Article  PubMed  CAS  Google Scholar 

  24. Jurisic V, Konjevic G, Banicevic B, Djuricic B, Spuzic I. Different alterations in lactate dehydrogenase (LDH) activity and profile of peripheral blood mononuclear cells in Hodgkin’s and non-Hodgkin’s lymphomas. Eur J Haematol. 2000;64:259–66. https://doi.org/10.1034/j.1600-0609.2000.90117.x.

    Article  PubMed  CAS  Google Scholar 

  25. Jurisic V, Radenkovic S, Konjevic G. The actual role of LDH as tumor marker, biochemical and clinical aspects. Adv Exp Med Biol. 2015;867:115–24. https://doi.org/10.1007/978-94-017-7215-0_8.

    Article  PubMed  CAS  Google Scholar 

  26. William BM, Bongu NR, Bast M, Bociek RG, Bierman PJ, Vose JM, Armitage JO. The utility of lactate dehydrogenase in the follow up of patients with diffuse large B-cell lymphoma. Rev Bras Hematol Hemoter. 2013;35:189–91. https://doi.org/10.5581/1516-8484.20130055.

    Article  PubMed  PubMed Central  Google Scholar 

  27. El-Hefnia A, Alazzazib N, Abu Taleb F. Prognostic utility of transforming growth factor beta-1 in diffuse large cell non-hodgkin lymphoma. J Hematol. 2015;4:131–6. https://doi.org/10.14740/jh194w.

    Article  CAS  Google Scholar 

  28. Pazgal I, Zimra Y, Tzabar C, Okon E, Rabizadeh E, Shaklai M, et al. Expression of basic fibroblast growth factor is associated with poor outcome in non-Hodgkin’s lymphoma. Br J Cancer. 2002;86:1770–5. https://doi.org/10.1038/sj.bjc.6600330.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Ghebremariam YT, Cooke JP, Gerhart W, Griego C, Brower JB, Doyle-Eisele M, et al. Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis. J Transl Med. 2015;13:249. https://doi.org/10.1186/s12967-015-0614-x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Nelson C, Lee J, Ko K, Sikora AG, Bonnen MD, Enkhbaatar P, et al. Therapeutic efficacy of esomeprazole in cotton smoke-induced lung injury model. Front Pharmacol. 2017;8:16. https://doi.org/10.3389/fphar.2017.00016.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Rivoltini L. Tumor-induced dysfunctions in adaptive and innate immunity: a novel therapeutic target for melanoma patients? Keio J Med. 2011;60

  32. Yeo M, Kim DK, Kim YB, Oh TY, Lee JE, Cho SW, et al. Selective induction of with proton pump inhibitor in gastric apoptosis cancer cells. Clin Cancer Res. 2004;10:8687–96. https://doi.org/10.1158/1078-0432.CCR-04-1065.

    Article  PubMed  CAS  Google Scholar 

  33. Ji L, Wang T, Tian L, Song H, Gao M. Roxatidine inhibits fibrosis by inhibiting NF-κB and MAPK signaling in macrophages sensing breast implant surface materials. Mol Med Rep. 2020;21:161–72. https://doi.org/10.3892/mmr.2019.10815.

    Article  PubMed  CAS  Google Scholar 

  34. Mandegari A, Gholami-Javadie A, Jafari M, Sabouri S. Synergistic therapeutic effects of cimetidine/famotidine in combination with doxorubicin on cancer cell lines. J Mazandaran Univ Med Sci. 2019;28:180–5.

    Google Scholar 

  35. Lv X, Feng L, Fang X, Jiang Y, Wang X. Overexpression of IL-9 receptor in diffuse large B cell lymphoma. Int J Clin Exp Pathol. 2013;6:911–6.

    PubMed  PubMed Central  CAS  Google Scholar 

  36. El Halawani N, El Sordi M, Aiad M, El Sabaa B, Hashim A. Diagnostic and prognostic value of nuclear factor kappa-B in diffuse large B cell lymphoma in Egyptian patients with hepatitis C virus genotype 4. Am J Mol Biol. 2019;9:121–43. https://doi.org/10.4236/ajmb.2019.93010.

    Article  CAS  Google Scholar 

  37. Kedika RR, Souza RF, Spechler SJ. Potential anti-inflammatory effects of proton pump inhibitors: a review and discussion of the clinical implications. Dig Dis Sci. 2009;54:2312–7. https://doi.org/10.1007/s10620-009-0951-9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Geeviman K, Babu D, Prakash BP. Pantoprazole induces mitochondrial apoptosis and attenuates NF-κB signaling in glioma cells. Cell Mol Neurobiol. 2018;38:1491–504. https://doi.org/10.1007/s10571-018-0623-4.

    Article  PubMed  CAS  Google Scholar 

  39. Balza E, Piccioli P, Carta S, Lavieri R, Gattorno M, Semino C, et al. Proton pump inhibitors protect mice from acute systemic inflammation and induce long-term cross-tolerance. Cell Death Dis. 2016;7:e2304. https://doi.org/10.1038/cddis.2016.218.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Feng LL, Gao JM, Li PP, Wang X. IL-9 contributes to immunosuppression mediated by regulatory T cells and mast cells in B cell non-hodgkin’s lymphoma. J Clin Immunol. 2011;31:1084–94. https://doi.org/10.1007/s10875-011-9584-9.

    Article  PubMed  CAS  Google Scholar 

  41. Elsawy WH, Abdel Kader M, Elfar A, Gharib A, Eltrhony S, Dorgham Y. Prognostic implications of caspase-3 expression in patients with diffuse large B cell lymphoma (DLBCL). J Clin Oncol. 2006;24:17500. https://doi.org/10.1200/jco.2006.24.18_suppl.17500.

    Article  Google Scholar 

  42. Yeo M, Kim DK, Park HJ, Cho SW, Cheong JY, Lee KJ. Retraction: blockage of intracellular proton extrusion with proton extrusions with proton pump inhibitor induces apoptosis in gastric cancer. Cancer Sci. 2008;99:185. https://doi.org/10.1111/j.1349-7006.2007.00642.x.

    Article  PubMed  CAS  Google Scholar 

  43. Yeo M, Kim DK, Han SU, Lee JE, Kim YB, Cho YK, et al. Novel action of gastric proton pump inhibitor on suppression of Helicobacter pylori induced angiogenesis. Gut. 2006;55:26–33. https://doi.org/10.1136/gut.2005.067454.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Shen Y, Chen M, Huang S, Zou X. Pantoprazole inhibits human gastric adenocarcinoma SGC-7901 cells by downregulating the expression of pyruvate kinase M2. Oncol Lett. 2016;11(1):717–22. https://doi.org/10.3892/ol.2015.3912.

    Article  PubMed  CAS  Google Scholar 

  45. Vard N, köroglu E, Tüzün S, Dolapçıoğlu C, Dabak R, . Comparison of the efficacies of proton pump inhibitors and H2 receptor antagonists in on-demand treatment of gastroesophageal reflux disease. Anatol JFM. 2018;1:8–12. https://doi.org/10.5505/anatoljfm.2018.87597.

    Article  Google Scholar 

Download references

Acknowledgements

The authors are grateful for the Oncology Department physicians at Menoufia University Hospital, Egypt, for permitting patients participation in this research and Faculty of Pharmacy at Tanta University for encouraging this research. The authors thank Dr. Maysa El-nagar for her assistance in biochemical analysis in this study and Dr. Suzy Gohar for her assistance in revising the manuscript.

Funding

This study did not take any specific donation from funding organizations in the public, commercial, or not-for-profit sections.

Author information

Authors and Affiliations

  1. Clinical Pharmacy Department, Faculty of Pharmacy, Tanta University, El-Guiesh Street, El-Gharbia Government, Tanta, 31527, Egypt

    Sahar K. Hegazy, Sahar M. El-Haggar & Eman I. El-berri

  2. Oncology and Nuclear Medicine Department, Faculty of Medicine, Menoufia University, Yassin Abdel Ghaffar St-from Gamal Abdel Anasar St, Shibin Elkom, Menoufia, 32511, Egypt

    Suzan A. Alhassanin

Authors
  1. Sahar K. Hegazy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sahar M. El-Haggar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suzan A. Alhassanin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eman I. El-berri
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SH: conceptualization, supervision, project administration; SE: supervision, project administration, writing-original draft; SA: conceptualization, data curation, visualization, investigation; EE: methodology, formal analysis, data curation, software, validation, writing-reviewing and editing.

Corresponding author

Correspondence to Eman I. El-berri.

Ethics declarations

Conflict of interest

All authors announce that they have no conflict of interest.

Ethical consent

Informed consent was obtained from all individual participants included in the study. Consent for publication is not applicable as there is no private data.

Ethical approval

The National Research Ethics Committee (Tanta University Ethical Committee) has approved the study and the study performance was compatible with the ethical standards of Helsinki declaration and its later amendments in the 1964).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hegazy, S.K., El-Haggar, S.M., Alhassanin, S.A. et al. Comparative randomized trial evaluating the effect of proton pump inhibitor versus histamine 2 receptor antagonist as an adjuvant therapy in diffuse large B-cell lymphoma. Med Oncol 38, 4 (2021). https://doi.org/10.1007/s12032-020-01452-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-020-01452-z

Keywords

Search

Navigation