Abstract
Background: Gastric cancer is a daunting global problem with unsatisfactory treatment. Due to the key role of Gastric Cancer Stem-like Cells (GCSCs) in all stages of gastric cancer and the failure of contemporary anticancer therapies, many research efforts are focusing on these treatmentresistant cells. Pantoprazole, as recently considered antitumor agent with well-documented effects on tumorigenesis inhibition, has seldom been investigated in GCSCs in previous studies. We aimed to study the influence of pantoprazole on cell proliferation, apoptosis, and the transcription of genes involved in the cell proliferation and apoptosis pathways.
Materials and Methods: Herein, we isolated GCSCs from MKN-45 cell line, on a non-adherent surface and then evaluated the effect of pantoprazole on cell growth and apoptosis of GCSCs by means of MTT, DNA laddering and quantitative real-time RT-PCR techniques.
Results: Our findings showed that treated cells with pantoprazole decreased cell proliferation and induced apoptosis. PCNA (Proliferating Cell Nuclear Antigen) and antiapoptotic Bcl2 genes were downregulated and Bax and CASP3 proapoptotic genes, as well as tumor suppressor p53 gene, were overexpressed.
Conclusion: Our results revealed that pantoprazole induced apoptosis and declined tumor growth and support the idea that pantoprazole played as a promising breakthrough in gastric cancer therapy.
Keywords: Gastric cancer, gastric cancer stem-like cells (GCSCs), pantoprazole, apoptosis, tumor growth, cell proliferation.
Graphical Abstract
[1]
Rawla P, Barsouk A. Epidemiology of gastric cancer: Global trends, risk factors and prevention. Prz Gastroenterol 2019; 14(1): 26-38.
[http://dx.doi.org/10.5114/pg.2018.80001] [PMID: 30944675]
[http://dx.doi.org/10.5114/pg.2018.80001] [PMID: 30944675]
[2]
Shah S, Underwood FE, Ng WK, et al. The global incidence of gastric cancer in the 21st century: A systematic review of population-based studies from 2007-2017. Gastroenterology 2018; 154(6): 986.
[3]
Molina-Castro S, Pereira-Marques J, Figueiredo C, Machado JC, Varon C. Gastric cancer: Basic aspects. Helicobacter 2017; 22 (Suppl. 1): e12412.
[http://dx.doi.org/10.1111/hel.12412] [PMID: 28891129]
[http://dx.doi.org/10.1111/hel.12412] [PMID: 28891129]
[4]
Li Y, Luo W, Li G, Liu Q, Liu Y, Sun L. Genistein induced apoptosis of gastric cancer cell through Bcl-2 and Caspase-3 regulation. Clin Oncol 2016; 1: 1150-6.
[5]
Shi W-J, Gao J-B. Molecular mechanisms of chemoresistance in gastric cancer. World J Gastrointest Oncol 2016; 8(9): 673-81.
[http://dx.doi.org/10.4251/wjgo.v8.i9.673] [PMID: 27672425]
[http://dx.doi.org/10.4251/wjgo.v8.i9.673] [PMID: 27672425]
[6]
Zhu JS, Wang L, Cheng GQ, Li Q, Zhu ZM, Zhu L. Apoptosis mechanisms of human gastric cancer cell line MKN-45 infected with human mutant p27. World J Gastroenterol 2005; 11(47): 7536-40.
[http://dx.doi.org/10.3748/wjg.v11.i47.7536] [PMID: 16437730]
[http://dx.doi.org/10.3748/wjg.v11.i47.7536] [PMID: 16437730]
[7]
Fulda S, Debatin K-M. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 2006; 25(34): 4798-811.
[http://dx.doi.org/10.1038/sj.onc.1209608] [PMID: 16892092]
[http://dx.doi.org/10.1038/sj.onc.1209608] [PMID: 16892092]
[8]
Takahashi T, Saikawa Y, Kitagawa Y. Gastric cancer: Current status of diagnosis and treatment. Cancers (Basel) 2013; 5(1): 48-63.
[http://dx.doi.org/10.3390/cancers5010048] [PMID: 24216698]
[http://dx.doi.org/10.3390/cancers5010048] [PMID: 24216698]
[9]
Fu Y, Du P, Zhao J, Hu C, Qin Y, Huang G. Gastric cancer stem cells: Mechanisms and therapeutic approaches. Yonsei Med J 2018; 59(10): 1150-8.
[http://dx.doi.org/10.3349/ymj.2018.59.10.1150] [PMID: 30450848]
[http://dx.doi.org/10.3349/ymj.2018.59.10.1150] [PMID: 30450848]
[10]
Shiozaki A, Marunaka Y, Otsuji E. Roles of ion and water channels in the cell death and survival of upper gastrointestinal tract cancers. Front Cell Dev Biol 2021; 9: 616933.
[http://dx.doi.org/10.3389/fcell.2021.616933] [PMID: 33777930]
[http://dx.doi.org/10.3389/fcell.2021.616933] [PMID: 33777930]
[11]
Cao Y, Chen M, Tang D, et al. The proton pump inhibitor pantoprazole disrupts protein degradation systems and sensitizes cancer cells to death under various stresses. Cell Death Dis 2018; 9(6): 604.
[http://dx.doi.org/10.1038/s41419-018-0642-6] [PMID: 29789637]
[http://dx.doi.org/10.1038/s41419-018-0642-6] [PMID: 29789637]
[12]
Zeng X, Liu L, Zheng M, et al. Pantoprazole, an FDA-approved proton-pump inhibitor, suppresses colorectal cancer growth by targeting T-cell-originated protein kinase. Oncotarget 2016; 7(16): 22460-73.
[http://dx.doi.org/10.18632/oncotarget.7984] [PMID: 26967058]
[http://dx.doi.org/10.18632/oncotarget.7984] [PMID: 26967058]
[13]
Lei W-Y, Wang J-H, Yi C-H, et al. Association between use of proton pump inhibitors and colorectal cancer: A nationwide population-based study. Clin Res Hepatol Gastroenterol 2021; 45(1): 101397.
[http://dx.doi.org/10.1016/j.clinre.2020.02.017] [PMID: 32224118]
[http://dx.doi.org/10.1016/j.clinre.2020.02.017] [PMID: 32224118]
[14]
Tran-Duy A, Spaetgens B, Hoes AW, de Wit NJ, Stehouwer CD. Use of proton pump inhibitors and risks of fundic gland polyps and gastric cancer: Systematic review and meta-analysis. Clin Gastroenterol Hepatol 2016; 14(12): 1706-19.
[http://dx.doi.org/10.1016/j.cgh.2016.05.018]
[http://dx.doi.org/10.1016/j.cgh.2016.05.018]
[15]
Koh JS, Joo MK, Park J-J, et al. Inhibition of STAT3 in gastric cancer: Role of pantoprazole as SHP-1 inducer. Cell Biosci 2018; 8(1): 50.
[http://dx.doi.org/10.1186/s13578-018-0248-9] [PMID: 30202514]
[http://dx.doi.org/10.1186/s13578-018-0248-9] [PMID: 30202514]
[16]
Shao Q, Xu J, Guan X, et al. in vitro and in vivo effects of miRNA-19b/20a/92a on gastric cancer stem cells and the related mechanism. Int J Med Sci 2018; 15(1): 86-94.
[http://dx.doi.org/10.7150/ijms.21164] [PMID: 29333091]
[http://dx.doi.org/10.7150/ijms.21164] [PMID: 29333091]
[17]
Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3(7): 730-7.
[http://dx.doi.org/10.1038/nm0797-730] [PMID: 9212098]
[http://dx.doi.org/10.1038/nm0797-730] [PMID: 9212098]
[18]
Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003; 63(18): 5821-8.
[PMID: 14522905]
[PMID: 14522905]
[19]
Takaishi S, Okumura T, Tu S, et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 2009; 27(5): 1006-20.
[http://dx.doi.org/10.1002/stem.30] [PMID: 19415765]
[http://dx.doi.org/10.1002/stem.30] [PMID: 19415765]
[20]
Chen W, Dong J, Haiech J, Kilhoffer M-C, Zeniou M. Cancer stem cell quiescence and plasticity as major challenges in cancer therapy. Stem cells international 2016; 2016.
[http://dx.doi.org/10.1155/2016/1740936]
[http://dx.doi.org/10.1155/2016/1740936]
[21]
Wang JC. Evaluating therapeutic efficacy against cancer stem cells: New challenges posed by a new paradigm. Cell Stem Cell 2007; 1(5): 497-501.
[http://dx.doi.org/10.1016/j.stem.2007.10.005] [PMID: 18938746]
[http://dx.doi.org/10.1016/j.stem.2007.10.005] [PMID: 18938746]
[22]
Liu J, Ma L, Xu J, et al. Spheroid body-forming cells in the human gastric cancer cell line MKN-45 possess cancer stem cell properties. Int J Oncol 2013; 42(2): 453-9.
[http://dx.doi.org/10.3892/ijo.2012.1720] [PMID: 23229446]
[http://dx.doi.org/10.3892/ijo.2012.1720] [PMID: 23229446]
[23]
Weglarz L, Molin I, Orchel A, Parfiniewicz B, Dzierzewicz Z. Quantitative analysis of the level of p53 and p21(WAF1) mRNA in human colon cancer HT-29 cells treated with inositol hexaphosphate. Acta Biochim Pol 2006; 53(2): 349-56.
[http://dx.doi.org/10.18388/abp.2006_3348] [PMID: 16733561]
[http://dx.doi.org/10.18388/abp.2006_3348] [PMID: 16733561]
[24]
Cheung KS, Leung WK. Long-term use of proton-pump inhibitors and risk of gastric cancer: A review of the current evidence. Therap Adv Gastroenterol 2019; 12: 1756284819834511.
[http://dx.doi.org/10.1177/1756284819834511] [PMID: 30886648]
[http://dx.doi.org/10.1177/1756284819834511] [PMID: 30886648]
[25]
Mahmoodi F, Akrami H. PlGF knockdown decreases tumorigenicity and stemness properties of spheroid body cells derived from gastric cancer cells. J Cell Biochem 2017; 118(4): 851-9.
[http://dx.doi.org/10.1002/jcb.25762] [PMID: 27735991]
[http://dx.doi.org/10.1002/jcb.25762] [PMID: 27735991]
[26]
Gupta PB, Onder TT, Jiang G, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 2009; 138(4): 645-59.
[http://dx.doi.org/10.1016/j.cell.2009.06.034] [PMID: 19682730]
[http://dx.doi.org/10.1016/j.cell.2009.06.034] [PMID: 19682730]
[27]
Gil J, Stembalska A, Pesz KA, Sąsiadek MM. Cancer stem cells: The theory and perspectives in cancer therapy. J Appl Genet 2008; 49(2): 193-9.
[http://dx.doi.org/10.1007/BF03195612] [PMID: 18436993]
[http://dx.doi.org/10.1007/BF03195612] [PMID: 18436993]
[28]
Tobinick EL. The value of drug repositioning in the current pharmaceutical market. Drug News Perspect 2009; 22(2): 119-25.
[http://dx.doi.org/10.1358/dnp.2009.22.2.1303818] [PMID: 19330170]
[http://dx.doi.org/10.1358/dnp.2009.22.2.1303818] [PMID: 19330170]
[29]
Joo MK, Park JJ, Chun HJ. Proton pump inhibitor: The dual role in gastric cancer. World J Gastroenterol 2019; 25(17): 2058-70.
[http://dx.doi.org/10.3748/wjg.v25.i17.2058] [PMID: 31114133]
[http://dx.doi.org/10.3748/wjg.v25.i17.2058] [PMID: 31114133]
[30]
Feng S, Zheng Z, Feng L, et al. Proton pump inhibitor pantoprazole inhibits the proliferation, self-renewal and chemoresistance of gastric cancer stem cells via the EMT/β catenin pathways. Oncol Rep 2016; 36(6): 3207-14.
[http://dx.doi.org/10.3892/or.2016.5154] [PMID: 27748935]
[http://dx.doi.org/10.3892/or.2016.5154] [PMID: 27748935]
[31]
Yeo M, Kim D-K, Kim Y-B, et al. Selective induction of apoptosis with proton pump inhibitor in gastric cancer cells. Clin Cancer Res 2004; 10(24): 8687-96.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-1065] [PMID: 15623654]
[http://dx.doi.org/10.1158/1078-0432.CCR-04-1065] [PMID: 15623654]
[32]
Segna D, Brusselaers N, Glaus D, Krupka N, Misselwitz B. Association between proton-pump inhibitors and the risk of gastric cancer: A systematic review with meta-analysis. Therap Adv Gastroenterol 2021; 14: 17562848211051463.
[http://dx.doi.org/10.1177/17562848211051463] [PMID: 34777575]
[http://dx.doi.org/10.1177/17562848211051463] [PMID: 34777575]
[33]
Yeo M, Kim DK, Park HJ, Cho SW, Cheong JY, Lee KJ. Retraction: Blockage of intracellular proton extrusion with proton pump inhibitor induces apoptosis in gastric cancer. Cancer Sci 2008; 99(1): 185.
[PMID: 17956591]
[PMID: 17956591]
[34]
Lopez J, Tait SW. Mitochondrial apoptosis: Killing cancer using the enemy within. Br J Cancer 2015; 112(6): 957-62.
[http://dx.doi.org/10.1038/bjc.2015.85] [PMID: 25742467]
[http://dx.doi.org/10.1038/bjc.2015.85] [PMID: 25742467]
[35]
Seo SI, Park CH, You SC, et al. Association between proton pump inhibitor use and gastric cancer: A population-based cohort study using two different types of nationwide databases in Korea. Gut 2021; 70(11): 2066-75.
[http://dx.doi.org/10.1136/gutjnl-2020-323845] [PMID: 33975868]
[http://dx.doi.org/10.1136/gutjnl-2020-323845] [PMID: 33975868]
[36]
Chueca E, Apostolova N, Esplugues JV, García-González MA, Lanas Á, Piazuelo E. Proton pump inhibitors display antitumor effects in Barrett’s adenocarcinoma cells. Front Pharmacol 2016; 7: 452.
[http://dx.doi.org/10.3389/fphar.2016.00452] [PMID: 27932981]
[http://dx.doi.org/10.3389/fphar.2016.00452] [PMID: 27932981]
[37]
De Milito A, Fais S. Proton pump inhibitors may reduce tumour resistance. Expert Opin Pharmacother 2005; 6(7): 1049-54.
[http://dx.doi.org/10.1517/14656566.6.7.1049] [PMID: 15957961]
[http://dx.doi.org/10.1517/14656566.6.7.1049] [PMID: 15957961]
[38]
Niikura R, Hayakawa Y, Hirata Y, Yamada A, Fujishiro M, Koike K. Long-term proton pump inhibitor use is a risk factor of gastric cancer after treatment for Helicobacter pylori: A retrospective cohort analysis. Gut 2018; 67(10): 1908-10.
[http://dx.doi.org/10.1136/gutjnl-2017-315710] [PMID: 29273641]
[http://dx.doi.org/10.1136/gutjnl-2017-315710] [PMID: 29273641]
[39]
Malfertheiner P, Kandulski A, Venerito M. Proton-pump inhibitors: Understanding the complications and risks. Nat Rev Gastroenterol Hepatol 2017; 14(12): 697-710.
[http://dx.doi.org/10.1038/nrgastro.2017.117] [PMID: 28930292]
[http://dx.doi.org/10.1038/nrgastro.2017.117] [PMID: 28930292]
Article Metrics
1