Abstract
Drug repositioning, as a smart way to exploit new molecular targets of a known drug, has been gaining increasing attention in the discovery of anti-cancer drugs. Proton pump inhibitors (PPIs) as benzimidazole derivatives, which are essentially H+–K+-ATPases inhibitors, are commonly used in the treatment of acid-related diseases such as gastric ulcer. In recent years, exploring the new application of PPIs in anti-cancer field has become a hot research topic. Interestingly, cancer cells display an alkaline intracellular pH and an acidic extracellular pH. The extracellular acidity of tumors can be corrected by PPIs that are selectively activated in an acid milieu. It is generally believed that PPIs might provoke disruption of pH homeostasis by targeting V-ATPase on cancer cells, which is the theoretical basis for PPIs to play an anti-cancer role. Numerous studies have shown specialized effects of the PPIs on tumor cell growth, metastasis, chemoresistance, and autophagy. PPIs may really represent new anti-cancer drugs due to better safety and tolerance, the potential selectivity in targeting tumor acidity, and the ability to inhibit mechanism pivotal for cancer homeostasis. In this review, we focus on the new therapeutic applications of PPIs in multiple cancers, explaining the rationale behind this approach and providing practical evidence.
Similar content being viewed by others
References
Tobinick EL (2009) The value of drug repositioning in the current pharmaceutical market. Drug News Perspect 22(2):119–125. doi:10.1358/dnp.2009.22.2.1303818
Rothwell PM, Price JF, Fowkes FG et al (2012) Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 379(9826):1602–1612. doi:10.1016/S0140-6736(11)61720-0
Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z (2012) Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 379(9826):1591–1601. doi:10.1016/S0140-6736(12)60209-8
Wurth R, Thellung S, Bajetto A, Mazzanti M, Florio T, Barbieri F (2016) Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds. Drug Discov Today 21(1):190–199. doi:10.1016/j.drudis.2015.09.017
Kwon D, Chae JB, Park CW et al (2001) Effects of IY-81149, a newly developed proton pump inhibitor, on gastric acid secretion in vitro and in vivo. Arzneimittelforschung 51(3):204–213. doi:10.1055/s-0031-1300026
Ji XQ, Du JF, Chen G, Chen G, Yu B (2014) Efficacy of ilaprazole in the treatment of duodenal ulcers: a meta-analysis. World J Gastroenterol 20(17):5119–5123. doi:10.3748/wjg.v20.i17.5119
Mirossay L, Mirossay A, Kocisova E, Radvakova I, Miskovsky P, Mojzis J (1999) 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 48(2):135–141
Luciani F, Spada M, De Milito A et al (2004) Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs. J Natl Cancer Inst 96(22):1702–1713. doi:10.1093/jnci/djh305
Breedveld P, Zelcer N, Pluim D et al (2004) Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug–drug interactions. Cancer Res 64(16):5804–5811. doi:10.1158/0008-5472.CAN-03-4062
Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033. doi:10.1126/science.1160809
Neri D, Supuran CT (2011) Interfering with pH regulation in tumors as a therapeutic strategy. Nat Rev Drug Discov 10(10):767–777. doi:10.1038/nrd3554
Fais S, De Milito A, You H, Qin W (2007) Targeting vacuolar H+-ATPases as a new strategy against cancer. Cancer Res 67(22):10627–10630. doi:10.1158/0008-5472.CAN-07-1805
Moriyama Y, Patel V, Ueda I, Futai M (1993) Evidence for a common binding site for omeprazole and N-ethylmaleimide in subunit A of chromaffin granule vacuolar-type H(+)-ATPase. Biochem Biophys Res Commun 196(2):699–706. doi:10.1006/bbrc.1993.2306
Chen M, Huang SL, Zhang XQ, Zhang B, Zhu H, Yang VW, Zou XP (2012) Reversal effects of pantoprazole on multidrug resistance in human gastric adenocarcinoma cells by down-regulating the V-ATPases/mTOR/HIF-1α/P-gp and MRP1 signaling pathway in vitro and in vivo. J Cell Biochem 113(7):2474–2487. doi:10.1002/jcb.24122
Spugnini EP, Citro G, Fais S (2010) Proton pump inhibitors as anti vacuolar-ATPases drugs: a novel anticancer strategy. J Exp Clin Cancer Res 29:44. doi:10.1186/1756-9966-29-44
Tavares-Valente D, Baltazar F, Moreira R, Queiros O (2013) Cancer cell bioenergetics and pH regulation influence breast cancer cell resistance to paclitaxel and doxorubicin. J Bioenerg Biomembr 45(5):467–475. doi:10.1007/s10863-013-9519-7
Abaza M, Luqmani YA (2013) The influence of pH and hypoxia on tumor metastasis. Expert Rev Anticancer Ther 13(10):1229–1242. doi:10.1586/14737140.2013.843455
Bellone M, Calcinotto A, Filipazzi P, De Milito A, Fais S, Rivoltini L (2013) The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors. Oncoimmunology 2(1):e22058. doi:10.4161/onci.22058
Song CW, Griffin R, Park HJ (2006) Influence of tumor pH on therapeutic response. In Teicher BA (ed) Cancer drug discovery and development: cancer drug resistance. Humana Press, Totowa, NJ, pp 21–42. doi:10.1007/978-1-59745-035-5_2
Park H, Lyons JC, Griffin RJ, Lim BU, Song CW (2000) Apoptosis and cell cycle progression in an acidic environment after irradiation. Radiat Res 153(3):295–304. doi:10.1038/sj.cdd.4400702
Park HJ, Lee SH, Chung H et al (2003) Influence of environmental pH on G2-phase arrest caused by ionizing radiation. Radiat Res 159(1):86–93. doi:10.1667/0033-7587(2003)159[0086:IOEPOG]2.0.CO;2
Lunt SJ, Chaudary N, Hill RP (2009) The tumor microenvironment and metastatic disease. Clin Exp Metastasis 26(1):19–34. doi:10.1007/s10585-008-9182-2
De Milito A, Fais S (2005) Tumor acidity, chemoresistance and proton pump inhibitors. Future Oncol 1(6):779–786. doi:10.2217/14796694.1.6.779
Thews O, Gassner B, Kelleher DK, Schwerdt G, Gekle M (2006) Impact of extracellular acidity on the activity of P-glycoprotein and the cytotoxicity of chemotherapeutic drugs. Neoplasia 8(2):143–152. doi:10.1593/neo.05697
Nishi T, Forgac M (2002) The vacuolar (H+)-ATPases—nature’s most versatile proton pumps. Nat Rev Mol Cell Biol 3(2):94–103. doi:10.1038/nrm729
Lu X, Qin W, Li J et al (2005) The growth and metastasis of human hepatocellular carcinoma xenografts are inhibited by small interfering RNA targeting to the subunit ATP6L of proton pump. Cancer Res 65(15):6843–6849. doi:10.1158/0008-5472.CAN-04-3822
Lim JH, Park JW, Kim MS, Park SK, Johnson RS, Chun YS (2006) Bafilomycin induces the p21-mediated growth inhibition of cancer cells under hypoxic conditions by expressing hypoxia-inducible factor-1α. Mol Pharmacol 70(6):1856–1865. doi:10.1124/mol.106.028076
Nakashima S, Hiraku Y, Tada-Oikawa S et al (2003) Vacuolar H+-ATPase inhibitor induces apoptosis via lysosomal dysfunction in the human gastric cancer cell line MKN-1. J Biochem 134(3):359–364. doi:10.1093/jb/mvg153
Sennoune SR, Bakunts K, Martinez GM, Chua-Tuan JL, Kebir Y, Attaya MN, Martinez-Zaguilan R (2004) Vacuolar H+-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity. Am J Physiol Cell Physiol 286(6):C1443–C1452. doi:10.1152/ajpcell.00407.2003
De Milito A, Canese R, Marino ML et al (2010) pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. Int J Cancer 127(1):207–219. doi:10.1002/ijc.25009
Perez-Sayans M, Somoza-Martin JM, Barros-Angueira F, Diz PG, Rey JM, Garcia-Garcia A (2010) Multidrug resistance in oral squamous cell carcinoma: the role of vacuolar ATPases. Cancer Lett 295(2):135–143. doi:10.1016/j.canlet.2010.03.019
Murakami T, Shibuya I, Ise T et al (2001) Elevated expression of vacuolar proton pump genes and cellular pH in cisplatin resistance. Int J Cancer 93(6):869–874. doi:10.1002/ijc.1418
You H, Jin J, Shu H et al (2009) Small interfering RNA targeting the subunit ATP6L of proton pump V-ATPase overcomes chemoresistance of breast cancer cells. Cancer Lett 280(1):110–119. doi:10.1016/j.canlet.2009.02.023
Mijaljica D, Prescott M, Devenish RJ (2011) V-ATPase engagement in autophagic processes. Autophagy 7(6):666–668. doi:10.4161/auto.7.6.15812
Mauvezin C, Neufeld TP (2015) Bafilomycin A1 disrupts autophagic flux by inhibiting both V-ATPase-dependent acidification and Ca-P60A/SERCA-dependent autophagosome-lysosome fusion. Autophagy 11(8):1437–1438. doi:10.1080/15548627.2015.1066957
Cruciat CM, Ohkawara B, Acebron SP, Karaulanov E, Reinhard C, Ingelfinger D, Boutros M, Niehrs C (2010) Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science 327(5964):459–463. doi:10.1126/science.1179802
Vaccari T, Duchi S, Cortese K, Tacchetti C, Bilder D (2010) The vacuolar ATPase is required for physiological as well as pathological activation of the Notch receptor. Development 137(11):1825–1832. doi:10.1242/dev.045484
Wiedmann RM, von Schwarzenberg K, Palamidessi A et al (2012) The V-ATPase-inhibitor archazolid abrogates tumor metastasis via inhibition of endocytic activation of the Rho-GTPase Rac1. Cancer Res 72(22):5976–5987. doi:10.1158/0008-5472.CAN-12-1772
von Schwarzenberg K, Lajtos T, Simon L, Muller R, Vereb G, Vollmar AM (2014) V-ATPase inhibition overcomes trastuzumab resistance in breast cancer. Mol Oncol 8(1):9–19. doi:10.1016/j.molonc.2013.08.011
Perez-Sayans M, Somoza-Martin JM, Barros-Angueira F, Rey JM, Garcia-Garcia A (2009) V-ATPase inhibitors and implication in cancer treatment. Cancer Treat Rev 35(8):707–713. doi:10.1016/j.ctrv.2009.08.003
Sachs G, Shin JM, Howden CW (2006) Review article: the clinical pharmacology of proton pump inhibitors. Aliment Pharmacol Ther 23(Suppl 2):2–8. doi:10.1111/j.1365-2036.2006.02943.x
Pauli-Magnus C, Rekersbrink S, Klotz U, Fromm MF (2001) Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein. Naunyn Schmiedebergs Arch Pharmacol 364(6):551–557. doi:10.1007/s00210-001-0489-7
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108. doi:10.3322/caac.21262
Yeo M, Kim DK, Kim YB, Oh TY, Lee JE, Cho SW, Kim HC, Hahm KB (2004) Selective induction of apoptosis with proton pump inhibitor in gastric cancer cells. Clin Cancer Res 10(24):8687–8696. doi:10.1158/1078-0432.CCR-04-1065
Gu M, Zhang Y, Zhou X, Ma H, Yao H, Ji F (2014) Rabeprazole exhibits antiproliferative effects on human gastric cancer cell lines. Oncol Lett 8(4):1739–1744. doi:10.3892/ol.2014.2354
Yeo M, Kim DK, Park HJ, Cho SW, Cheong JY, Lee KJ (2008) Retraction: blockage of intracellular proton extrusion with proton pump inhibitor induces apoptosis in gastric cancer. Cancer Sci 99(1):185. doi:10.1111/j.1349-7006.2007.00642.x
Shen Y, Wu Y, Chen M, Shen W, Huang S, Zhang L, Zou X (2012) Effects of pantoprazole as a HIF-1α inhibitor on human gastric adenocarcinoma sgc-7901 cells. Neoplasma 59(2):142–149. doi:10.4149/neo_2012_019
Shen Y, Chen M, Huang S, Zou X (2016) Pantoprazole inhibits human gastric adenocarcinoma SGC-7901 cells by downregulating the expression of pyruvate kinase M2. Oncol Lett 11(1):717–722. doi:10.3892/ol.2015.3912
Shen W, Zou X, Chen M, Shen Y, Huang S, Guo H, Zhang L, Liu P (2013) Effect of pantoprazole on human gastric adenocarcinoma SGC7901 cells through regulation of phosphor-LRP6 expression in Wnt/β-catenin signaling. Oncol Rep 30(2):851–855. doi:10.3892/or.2013.2524
Zhang B, Yang Y, Shi X et al (2015) Proton pump inhibitor pantoprazole abrogates adriamycin-resistant gastric cancer cell invasiveness via suppression of Akt/GSK-β/β-catenin signaling and epithelial-mesenchymal transition. Cancer Lett 356(2):704–712. doi:10.1016/j.canlet.2014.10.016
Chen M, Zou X, Luo H, Cao J, Zhang X, Zhang B, Liu W (2009) Effects and mechanisms of proton pump inhibitors as a novel chemosensitizer on human gastric adenocarcinoma (SGC7901) cells. Cell Biol Int 33(9):1008–1019. doi:10.1016/j.cellbi.2009.05.004
Huang S, Chen M, Ding X, Zhang X, Zou X (2013) Proton pump inhibitor selectively suppresses proliferation and restores the chemosensitivity of gastric cancer cells by inhibiting STAT3 signaling pathway. Int Immunopharmacol 17(3):585–592. doi:10.1016/j.intimp.2013.07.021
Kim YJ, Lee JS, Hong KS, Chung JW, Kim JH, Hahm KB (2010) Novel application of proton pump inhibitor for the prevention of colitis-induced colorectal carcinogenesis beyond acid suppression. Cancer Prev Res (Phila) 3(8):963–974. doi:10.1158/1940-6207.CAPR-10-0033
Patlolla JM, Zhang Y, Li Q, Steele VE, Rao CV (2012) Anti-carcinogenic properties of omeprazole against human colon cancer cells and azoxymethane-induced colonic aberrant crypt foci formation in rats. Int J Oncol 40(1):170–175. doi:10.3892/ijo.2011.1214
Zlobec I, Molinari F, Kovac M et al (2010) Prognostic and predictive value of TOPK stratified by KRAS and BRAF gene alterations in sporadic, hereditary and metastatic colorectal cancer patients. Br J Cancer 102(1):151–161. doi:10.1038/sj.bjc.6605452
Zeng X, Liu L, Zheng M et al (2016) Pantoprazole, an FDA-approved proton-pump inhibitor, suppresses colorectal cancer growth by targeting T-cell-originated protein kinase. Oncotarget 7(16):22460–22473. doi:10.18632/oncotarget.7984
Lindner K, Borchardt C, Schopp M, Burgers A, Stock C, Hussey DJ, Haier J, Hummel R (2014) Proton pump inhibitors (PPIs) impact on tumour cell survival, metastatic potential and chemotherapy resistance, and affect expression of resistance-relevant miRNAs in esophageal cancer. J Exp Clin Cancer Res 33:73. doi:10.1186/s13046-014-0073-x
Miyashita T, Shah FA, Marti GP et al (2011) Rabeprazole impedes the development of reflux-induced esophageal cancer in a surgical rat model. Dig Dis Sci 56(5):1309–1314. doi:10.1007/s10620-010-1465-1
El-Serag HB, Aguirre TV, Davis S, Kuebeler M, Bhattacharyya A, Sampliner RE (2004) Proton pump inhibitors are associated with reduced incidence of dysplasia in Barrett’s esophagus. Am J Gastroenterol 99(10):1877–1883. doi:10.1111/j.1572-0241.2004.30228.x
Uwagawa T, Misawa T, Iida T, Sakamoto T, Gocho T, Wakiyama S, Hirohara S, Yanaga K (2010) Proton-pump inhibitor as palliative care for chemotherapy-induced gastroesophageal reflux disease in pancreatic cancer patients. J Palliat Med 13(7):815–818. doi:10.1089/jpm.2009.0404
Udelnow A, Kreyes A, Ellinger S et al (2011) Omeprazole inhibits proliferation and modulates autophagy in pancreatic cancer cells. PLoS One 6(5):e20143. doi:10.1371/journal.pone.0020143
Fako VE, Wu X, Pflug B, Liu JY, Zhang JT (2015) Repositioning proton pump inhibitors as anticancer drugs by targeting the thioesterase domain of human fatty acid synthase. J Med Chem 58(2):778–784. doi:10.1021/jm501543u
Alo PL, Amini M, Piro F et al (2007) Immnunohistochemical expression and prognostic significance of fatty acid synthase in pancreatic carcinoma. Anticancer Res 27(4B):2523–2527
Jin UH, Kim SB, Safe S (2015) Omeprazole inhibits pancreatic cancer cell invasion through a nongenomic aryl hydrocarbon receptor pathway. Chem Res Toxicol 28(5):907–918. doi:10.1021/tx5005198
Dent R, Trudeau M, Pritchard KI et al (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13(15 Pt 1):4429–4434. doi:10.1158/1078-0432.CCR-06-3045
Goh W, Sleptsova-Freidrich I, Petrovic N (2014) Use of proton pump inhibitors as adjunct treatment for triple-negative breast cancers. An introductory study. J Pharm Pharm Sci 17(3):439–446
Zhang S, Wang Y, Li SJ (2014) Lansoprazole induces apoptosis of breast cancer cells through inhibition of intracellular proton extrusion. Biochem Biophys Res Commun 448(4):424–429. doi:10.1016/j.bbrc.2014.04.127
Yu M, Lee C, Wang M, Tannock IF (2015) Influence of the proton pump inhibitor lansoprazole on distribution and activity of doxorubicin in solid tumors. Cancer Sci 106(10):1438–1447. doi:10.1111/cas.12756
Patel KJ, Lee C, Tan Q, Tannock IF (2013) Use of the proton pump inhibitor pantoprazole to modify the distribution and activity of doxorubicin: a potential strategy to improve the therapy of solid tumors. Clin Cancer Res 19(24):6766–6776. doi:10.1158/1078-0432.CCR-13-0128
Jin UH, Lee SO, Pfent C, Safe S (2014) The aryl hydrocarbon receptor ligand omeprazole inhibits breast cancer cell invasion and metastasis. BMC Cancer 14:498. doi:10.1186/1471-2407-14-498
Matsuo K, Lin YG, Roman LD, Sood AK (2010) Overcoming platinum resistance in ovarian carcinoma. Expert Opin Investig Drugs 19(11):1339–1354. doi:10.1517/13543784.2010.515585
Lee YY, Jeon HK, Hong JE et al (2015) Proton pump inhibitors enhance the effects of cytotoxic agents in chemoresistant epithelial ovarian carcinoma. Oncotarget 6(33):35040–35050. doi:10.18632/oncotarget.5319
Tan Q, Joshua AM, Saggar JK et al (2015) Effect of pantoprazole to enhance activity of docetaxel against human tumour xenografts by inhibiting autophagy. Br J Cancer 112(5):832–840. doi:10.1038/bjc.2015.17
Yang ZJ, Chee CE, Huang S, Sinicrope FA (2011) The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther 10(9):1533–1541. doi:10.1158/1535-7163.MCT-11-0047
Karavan M, Compton N, Knezevich S, Raugi G, Kodama S, Taylor L, Reiber GE (2014) Teledermatology in the diagnosis of melanoma. J Telemed Telecare 20(1):18–23. doi:10.1177/1357633X13517354
Azzarito T, Venturi G, Cesolini A, Fais S (2015) Lansoprazole induces sensitivity to suboptimal doses of paclitaxel in human melanoma. Cancer Lett 356(2 Pt B):697–703. doi:10.1016/j.Canlet.2014.10.017
Marino ML, Fais S, Djavaheri-Mergny M et al (2010) Proton pump inhibition induces autophagy as a survival mechanism following oxidative stress in human melanoma cells. Cell Death Dis 1:e87. doi:10.1038/cddis.2010.67
Lugini L, Federici C, Borghi M, Azzarito T, Marino ML, Cesolini A, Spugnini EP, Fais S (2016) Proton pump inhibitors while belonging to the same family of generic drugs show different anti-tumor effect. J Enzyme Inhib Med Chem 31(4):538–545. doi:10.3109/14756366.2015.1046062
Marcotte EL, Ritz B, Cockburn M, Clarke CA, Heck JE (2014) Birth characteristics and risk of lymphoma in young children. Cancer Epidemiol 38(1):48–55. doi:10.1016/j.canep.2013.11.005
Scaringi L, Cornacchione P, Ayroldi E, Corazzi L, Capodicasa E, Rossi R, Marconi P (2004) Omeprazole induces apoptosis in jurkat cells. Int J Immunopathol Pharmacol 17(3):331–342. doi:10.1177/039463200401700313
De Milito A, Iessi E, Logozzi M et al (2007) Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species. Cancer Res 67(11):5408–5417. doi:10.1158/0008-5472.CAN-06-4095
Vishvakarma NK, Singh SM (2011) Mechanisms of tumor growth retardation by modulation of pH regulation in the tumor-microenvironment of a murine T cell lymphoma. Biomed Pharmacother 65(1):27–39. doi:10.1016/j.biopha.2010.06.012
Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67(1):7–30. doi:10.3322/caac.21387
White DL, Eadie LN, Saunders VA, Hiwase DK, Hughes TP (2013) Proton pump inhibitors significantly increase the intracellular concentration of nilotinib, but not imatinib in target CML cells. Leukemia 27(5):1201–1204. doi:10.1038/leu.2012.295
Yin OQ, Giles FJ, Baccarani M et al (2012) Concurrent use of proton pump inhibitors or H2 blockers did not adversely affect nilotinib efficacy in patients with chronic myeloid leukemia. Cancer Chemother Pharmacol 70(2):345–350. doi:10.1007/s00280-012-1881-3
Dimopoulos MA, San-Miguel JF, Anderson KC (2011) Emerging therapies for the treatment of relapsed or refractory multiple myeloma. Eur J Haematol 86(1):1–15. doi:10.1111/j.1600-0609.2010.01542.x
Canitano A, Iessi E, Spugnini EP, Federici C, Fais S (2016) Proton pump inhibitors induce a caspase-independent antitumor effect against human multiple myeloma. Cancer Lett 376(2):278–283. doi:10.1016/j.canlet.2016.04.015
Stiller CA, Trama A, Serraino D, Rossi S, Navarro C, Chirlaque MD, Casali PG (2013) Descriptive epidemiology of sarcomas in Europe: report from the RARECARE project. Eur J Cancer 49(3):684–695. doi:10.1016/j.ejca.2012.09.011
Marina N, Gebhardt M, Teot L, Gorlick R (2004) Biology and therapeutic advances for pediatric osteosarcoma. Oncologist 9(4):422–441. doi:10.1634/theoncologist.9-4-422
Ferrari S, Perut F, Fagioli F et al (2013) Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients’ bed. J Transl Med 11:268. doi:10.1186/1479-5876-11-268
Wang BY, Zhang J, Wang JL et al (2015) Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer. J Exp Clin Cancer Res 34:85. doi:10.1186/s13046-015-0194-x
Brana I, Ocana A, Chen EX et al (2014) A phase I trial of pantoprazole in combination with doxorubicin in patients with advanced solid tumors: evaluation of pharmacokinetics of both drugs and tissue penetration of doxorubicin. Invest New Drugs 32(6):1269–1277. doi:10.1007/s10637-014-0159-5
Marchetti P, Milano A, D’Antonio C, Romiti A, Falcone R, Roberto M, Fais S (2016) 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 15(4):377–380. doi:10.1016/j.clcc.2016.06.005
Spugnini EP, Baldi A, Buglioni S et al (2011) Lansoprazole as a rescue agent in chemoresistant tumors: a phase I/II study in companion animals with spontaneously occurring tumors. J Transl Med 9:221. doi:10.1186/1479-5876-9-221
Spugnini EP, Buglioni S, Carocci F, Francesco M, Vincenzi B, Fanciulli M, Fais S (2014) High dose lansoprazole combined with metronomic chemotherapy: a phase I/II study in companion animals with spontaneously occurring tumors. J Transl Med 12:225. doi:10.1186/s12967-014-0225-y
Attila T, Santharam R, Blom D, Komorowski R, Koch TR (2005) Multifocal gastric carcinoid tumor in a patient with pernicious anemia receiving lansoprazole. Dig Dis Sci 50(3):509–513. doi:10.1007/s10620-005-2466-3
Jianu CS, Lange OJ, Viset T et al (2012) Gastric neuroendocrine carcinoma after long-term use of proton pump inhibitor. Scand J Gastroenterol 47(1):64–67. doi:10.3109/00365521.2011.627444
Ko Y, Tang J, Sanagapalli S, Kim BS, Leong RW (2016) Safety of proton pump inhibitors and risk of gastric cancers: review of literature and pathophysiological mechanisms. Expert Opin Drug Saf 15(1):53–63. doi:10.1517/14740338.2016.1118050
Acknowledgements
This work was funded by the National Science Foundation of China Grants (81373450) and Major Project of Science and Technology of Shandong Province (2015ZDJS04001, 2015ZDXX0301A03).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Rights and permissions
About this article
Cite this article
Lu, ZN., Tian, B. & Guo, XL. Repositioning of proton pump inhibitors in cancer therapy. Cancer Chemother Pharmacol 80, 925–937 (2017). https://doi.org/10.1007/s00280-017-3426-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-017-3426-2