The Evaluation of Potential Cytotoxic Effect of Different Proton Pump Inhibitors on Different Human Cancer Cell Lines

Author(s): Aya Qasem, Violet Kasabri, Eman AbuRish, Yasser Bustanji*, Yusuf Al-Hiari, Reem Al-Abbasi, Bashaer Abu-Irmaileh, Sundus Alalawi

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 2 , 2020

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Abstract:

Objective: To assess the differential cytotoxic activity of PPIs on different human cancer cell lines; namely A549 lung cancer, CACO-2 colorectal cancer, MCF-7 breast cancer, and PANC-1 pancreatic cancer, A375 skin melanoma.

Methods: In this study, the five human cancer cell lines and human non-cancerous fibroblasts were treated with increasing concentration of PPIs Omeprazole (OMP), Esomeprazole (ESOM), and Lansoprazole (LANSO) (50-300μM), over 24h, 48h, and 72h. Cell viability was determined using 3-(4,5- Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and the IC50 values of PPIs were measured. The most sensitive cell line A375 was used for further investigation. The cytotoxic effects of LANSO on these cells were assessed using Annexin-V Propidium Iodide (AV-PI) flow cytometry. As of action mechanism; anti-inflammatory effects of each PPIs and PPIs-DOXO combination therapy on LPS-stimulated RAW 264.7 mouse macrophages were assessed.

Results: Dose and time dependence cytotoxic activity of PPIs on human cancer cell lines was founded. Unlike DOXO; All PPIs had a selective cytotoxic effect in the normal fibroblasts. Unlike the equipotent OMP and ESOM; LANSO was the most potent drug with IC50 values at 72h of 99, 217, 272, 208, 181μM against A375, A549, CACO-2, MCF-7, and PANC-1, respectively. AV-PI flow cytometry revealed dose-dependent apoptotic effects of LANSO alone and substantially enhanced in DOXO-co-treatments. Interestingly unlike ESOM and OMP, LANSO proved more effective than indomethacin in LPS-stimulated RAW 264.7 macrophages. None of the tested compounds, as well as indomethacin, exerted any cytotoxicity against RAW 264.7 macrophages. PPIs-DOXO lacked potential synergistic combination antiinflammation therapies.

Conclusion: This study provides the evidence that PPIs induce a direct and differential cytotoxic activity against human cancer cell line by the induction of the apoptosis. Moreover, PPIs increase cancer cell lines sensitivity to doxorubicin via apoptosis augmentation. Nevertheless, PPIs-DOXO lacked potential synergistic combination therapies in either antiproliferation or anti-inflammation.

Keywords: Proton pump inhibitors, human melanoma cell line A375, apoptosis and Annexin-V propidium iodide, differential cytotoxicity, doxorubicin, fibroblasts.

[1]
American Cancer Society, Key Statistics for Cancer. https://www.cancer.org/cancer.html (Accessed March 20, 2019)
[2]
Canitano, A.; Iessi, E.; Spugnini, E.P.; Federici, C.; Fais, S. Proton pump inhibitors induce a caspase-independent antitumor effect against human multiple myeloma. Cancer Lett., 2016, 376(2), 278-283.
[http://dx.doi.org/10.1016/j.canlet.2016.04.015] [PMID: 27084522]
[3]
Fais, S. Evidence-based support for the use of proton pump inhibitors in cancer therapy. J. Transl. Med., 2015, 13, 368-368.
[http://dx.doi.org/10.1186/s12967-015-0735-2] [PMID: 26597250]
[4]
Ferrari, S.; Perut, F.; Fagioli, F.; Brach Del Prever, A.; Meazza, C.; Parafioriti, A.; Picci, P.; Gambarotti, M.; Avnet, S.; Baldini, N.; Fais, S. Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients’ bed. J. Transl. Med., 2013, 11, 268.
[http://dx.doi.org/10.1186/1479-5876-11-268] [PMID: 24156349]
[5]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: the next generation. Cell, 2011, 144(5), 646-674.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[6]
Walsh, M.; Fais, S.; Spugnini, E.P.; Harguindey, S.; Abu Izneid, T.; Scacco, L.; Williams, P.; Allegrucci, C.; Rauch, C.; Omran, Z. Proton pump inhibitors for the treatment of cancer in companion animals. J. Exp. Clin. Cancer Res., 2015, 34, 93.
[http://dx.doi.org/10.1186/s13046-015-0204-z] [PMID: 26337905]
[7]
Lee, Y.Y.; Jeon, H.K.; Hong, J.E.; Cho, Y.J.; Ryu, J.Y.; Choi, J.J.; Lee, S.H.; Yoon, G.; Kim, W.Y.; Do, I.G.; Kim, M.K.; Kim, T.J.; Choi, C.H.; Lee, J.W.; Bae, D.S.; Kim, B.G. Proton pump inhibitors enhance the effects of cytotoxic agents in chemoresistant epithelial ovarian carcinoma. Oncotarget, 2015, 6(33), 35040-35050.
[http://dx.doi.org/10.18632/oncotarget.5319] [PMID: 26418900]
[8]
Maxson, M.E.; Grinstein, S. The vacuolar-type H+-ATPase at a glance - more than a proton pump. J. Cell Sci., 2014, 127(Pt 23), 4987-4993.
[http://dx.doi.org/10.1242/jcs.158550] [PMID: 25453113]
[9]
Taylor, S.; Spugnini, E.P.; Assaraf, Y.G.; Azzarito, T.; Rauch, C.; Fais, S. Microenvironment acidity as a major determinant of tumor chemoresistance: Proton pump inhibitors (PPIs) as a novel therapeutic approach. Drug Resist. Updat., 2015, 23, 69-78.
[http://dx.doi.org/10.1016/j.drup.2015.08.004] [PMID: 26341193]
[10]
Riaz, S.; Nasim, A. Proton pump inhibitors use; beware of side-effects. J. Pak. Med. Assoc., 2016, 66(12), 1672.
[PMID: 27924970]
[11]
Shin, J.M.; Sachs, G. Pharmacology of proton pump inhibitors. Curr. Gastroenterol. Rep., 2008, 10(6), 528-534.
[http://dx.doi.org/10.1007/s11894-008-0098-4] [PMID: 19006606]
[12]
Wong, R.S. Apoptosis in cancer: from pathogenesis to treatment. J. Exp. Clin. Cancer Res., 2011, 30(1), 87.
[http://dx.doi.org/10.1186/1756-9966-30-87] [PMID: 21943236]
[13]
(a)Patlolla, J.M.; Zhang, Y.; Li, Q.; Steele, V.E.; Rao, C.V. Anti-carcinogenic properties of omeprazole against human colon cancer cells and azoxymethane-induced colonic aberrant crypt foci formation in rats. Int. J. Oncol., 2012, 40(1), 170-175.
[PMID: 21956158]
(b)Jin, U.H.; Kim, S.B.; Safe, S. Omeprazole inhibits pancreatic cancer cell invasion through a nongenomic aryl hydrocarbon receptor pathway. Chem. Res. Toxicol., 2015, 28(5), 907-918.
[http://dx.doi.org/10.1021/tx5005198] [PMID: 25826687]
(c)Lindner, K.; Borchardt, C.; Schöpp, M.; Bürgers, A.; Stock, C.; Hussey, D.J.; Haier, J.; Hummel, R. 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., 2014, 33(1), 73-73.
[http://dx.doi.org/10.1186/s13046-014-0073-x] [PMID: 25175076]
[14]
Park, H.K.; Lee, J.E.; Lim, J.; Jo, D.E.; Park, S.A.; Suh, P.G.; Kang, B.H. Combination treatment with doxorubicin and gamitrinib synergistically augments anticancer activity through enhanced activation of Bim. BMC Cancer, 2014, 14, 431.
[http://dx.doi.org/10.1186/1471-2407-14-431] [PMID: 24927938]
[15]
Patel, K.J.; Lee, C.; Tan, Q.; Tannock, I.F. 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., 2013, 19(24), 6766-6776.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-0128] [PMID: 24141627]
[16]
Oral, A.; Oral, H.; Sarimahmut, M.; Cevatemre, B.; Özkaya, G.; Korkmaz, S.; Ulukaya, E. Combination of esomeprazole with chemotherapeutics results in more pronounced cytotoxic effect via apoptosis on A549 nonsmall-cell lung cancer cell line. Turk. J. Biol., 2017, 41, 231-241.
[http://dx.doi.org/10.3906/biy-1606-46]
[17]
Ritter, B.; Greten, F.R. Modulating inflammation for cancer therapy. J. Exp. Med., 2019, 216(6), 1234-1243.
[http://dx.doi.org/10.1084/jem.20181739] [PMID: 31023715]
[18]
Comen, E.A.; Bowman, R.L.; Kleppe, M. Underlying causes and therapeutic targeting of the inflammatory tumor microenvironment. Front. Cell Dev. Biol., 2018, 6, 56.
[http://dx.doi.org/10.3389/fcell.2018.00056] [PMID: 29946544]
[19]
Coussens, L.M.; Werb, Z. Inflammation and cancer. Nature, 2002, 420(6917), 860-867.
[http://dx.doi.org/10.1038/nature01322] [PMID: 12490959]
[20]
Sulciner, M.L.; Serhan, C.N.; Gilligan, M.M.; Mudge, D.K.; Chang, J.; Gartung, A.; Lehner, K.A.; Bielenberg, D.R.; Schmidt, B.; Dalli, J.; Greene, E.R.; Gus-Brautbar, Y.; Piwowarski, J.; Mammoto, T.; Zurakowski, D.; Perretti, M.; Sukhatme, V.P.; Kaipainen, A.; Kieran, M.W.; Huang, S.; Panigrahy, D. Resolvins suppress tumor growth and enhance cancer therapy. J. Exp. Med., 2018, 215(1), 115-140.
[http://dx.doi.org/10.1084/jem.20170681] [PMID: 29191914]
[21]
Moro, K.; Nagahashi, M.; Ramanathan, R.; Takabe, K.; Wakai, T. Resolvins and omega three polyunsaturated fatty acids: Clinical implications in inflammatory diseases and cancer. World J. Clin. Cases, 2016, 4(7), 155-164.
[http://dx.doi.org/10.12998/wjcc.v4.i7.155] [PMID: 27458590]
[22]
Vichai, V.; Kirtikara, K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat. Protoc., 2006, 1(3), 1112-1116.
[http://dx.doi.org/10.1038/nprot.2006.179] [PMID: 17406391]
[23]
Assanga, S.B.I.; Luján, L.M.L.; Gil-Salido, A.A.; Espinoza, C.L.L.; Angulo, D.F.; Rubio-Pino, J.L.; Riera, R.B. Anti-inflammatory activity and modulate oxidative stress of Bucida buceras in lipopolysaccharide-stimulated RAW 264.7 macrophages and Carrageenan-induced acute paw edema in rats. J. Med. Plants Res., 2017, 239-252.
[24]
Huang, J.; Wang, Y.; Li, C.; Wang, X.; He, X. Anti-inflammatory oleanolic triterpenes from Chinese acorns. Molecules, 2016, 21(5), 669.
[http://dx.doi.org/10.3390/molecules21050669] [PMID: 27213322]
[25]
Lugini, L.; Federici, C.; Borghi, M.; Azzarito, T.; Lucia, Marino.M.; Cesolini, A.; Spugnini, E.P.; Fais, S. Proton pump inhibitors while belonging to the same family of generic drugs show different anti-tumor effect. J. Enzyme Inhib. Med. Chem., 2016, 31(4), 538-545.
[PMID: 26018420]
[26]
Awortwe, C.; Fasinu, P.S.; Rosenkranz, B. Application of Caco-2 cell line in herb-drug interaction studies: current approaches and challenges. J. Pharm. Pharm. Sci., 2014, 17(1), 1-19.
[http://dx.doi.org/10.18433/J30K63] [PMID: 24735758]
[27]
De Milito, A.; Marino, M.L.; Fais, S. A rationale for the use of proton pump inhibitors as antineoplastic agents. Curr. Pharm. Des., 2012, 18(10), 1395-1406.
[http://dx.doi.org/10.2174/138161212799504911] [PMID: 22360553]
[28]
Lai, S.W.; Sung, F.C.; Lin, C.L.; Liao, K.F. Use of proton pump inhibitors correlates with increased risk of pancreatic cancer: A case-control study in Taiwan. Kuwait Med. J., 2014, 46, 44-48.
[29]
Numico, G.; Fusco, V.; Franco, P.; Roila, F. Proton Pump Inhibitors in cancer patients: How useful they are? A review of the most common indications for their use. Crit. Rev. Oncol. Hematol., 2017, 111, 144-151.
[http://dx.doi.org/10.1016/j.critrevonc.2017.01.014] [PMID: 28259289]
[30]
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.
[http://dx.doi.org/10.3389/fphar.2017.00911] [PMID: 29311921]
[31]
Huang, L.; Jiang, Y.; Chen, Y. Predicting drug combination index and simulating the network-regulation dynamics by mathematical modeling of drug-targeted EGFR-ERK signaling pathway. Sci. Rep., 2017, 7, 40752.
[http://dx.doi.org/10.1038/srep40752] [PMID: 28102344]
[32]
Tokarska-Schlattner, M.; Zaugg, M.; da Silva, R.; Lucchinetti, E.; Schaub, M.C.; Wallimann, T.; Schlattner, U. Acute toxicity of doxorubicin on isolated perfused heart: response of kinases regulating energy supply. Am. J. Physiol. Heart Circ. Physiol., 2005, 289(1), H37-H47.
[http://dx.doi.org/10.1152/ajpheart.01057.2004] [PMID: 15764680]
[33]
Albouy, B.; Tourani, J.M.; Allain, P.; Rolland, F.; Staerman, F.; Eschwege, P.; Pfister, C. Preliminary results of the Prostacox phase II trial in hormonal refractory prostate cancer. BJU Int., 2007, 100(4), 770-774.
[http://dx.doi.org/10.1111/j.1464-410X.2007.07095.x] [PMID: 17822458]
[34]
Rayburn, E.R.; Ezell, S.J.; Zhang, R. Anti-inflammatory agents for cancer therapy. Mol. Cell. Pharmacol., 2009, 1(1), 29-43.
[http://dx.doi.org/10.4255/mcpharmacol.09.05] [PMID: 20333321]
[35]
Ichimaru, S.; Nakagawa, S.; Arai, Y.; Tsuchida, S.; Inoue, H.; Matsuki, T.; Taniguchi, D.; Oda, R.; Fujiwara, H.; Kubo, T. Anti-inflammatory effects of lansoprazole by inhibiting nitric oxide production via reactive oxygen species in murine macrophage raw 264.7 cells; Osteoarthr Cartil, 2014.
[36]
Handa, O.; Yoshida, N.; Fujita, N.; Tanaka, Y.; Ueda, M.; Takagi, T.; Kokura, S.; Naito, Y.; Okanoue, T.; Yoshikawa, T. Molecular mechanisms involved in anti-inflammatory effects of proton pump inhibitors. Inflamm. Res., 2006, 55(11), 476-480.
[http://dx.doi.org/10.1007/s00011-006-6056-4] [PMID: 17122965]


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Article Details

VOLUME: 20
ISSUE: 2
Year: 2020
Published on: 24 April, 2020
Page: [245 - 253]
Pages: 9
DOI: 10.2174/1871520619666191029151545
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