Ethanol extracts of Allium sp. regulate cyclooxygenase-2 and E-cadherin expression in gastric cancer MKN74 cell line and enhance doxorubicin toxicity
Background: Gastric cancer (GC) remains one of the leading causes of cancer-related death. Its aetiology is multifactorial, but the major risk factor is a high in salt diet. During gastric carcinogenesis, cadherin-1 (CDH1) down-expression and cyclooxygenase 2 (COX2) overexpression may be observed. The intensity of these alterations contributes to the GC invasion, its metastases and poor prognosis. As the diet plays a significant role in the aetiology of GC, it is reasonable to include the nutritional chemoprevention agents. One of the plant genus demonstrating chemoprotective properties is Allium genus, which includes garlic. The relationship between CDH1 and COX2 in GC cells treated with Allium species extract has never been evaluated.
Methods: In this study, the MKN28 and MKN74 GC cell lines were treated with ethanol extracts of Allium angulosum L., Allium lusitanicum Lam., Allium sativum L. (from Malaysia and Poland), Allium tibeticum Rendle and Allium ursinum L. The cytotoxicity of the extracts and their influence on COX2 and CDH1 mRNA and protein expression were evaluated as well as their influence on doxorubicin’s (DOX) efficacy – a drug that has been used in GC treatment.
Results: Among the tested species, ethanol extracts of A. sativum L. (Poland and Malaysia), A. tibeticum Rendle and A. ursinum L. influenced the levels of CDH1 and COX2, but only in the MKN74 cell line. Thus, it is possible that tumours with increased COX2 expression will be more susceptible to garlic treatment. Observed phenomenon was independent of Allium extract’s toxicity. In comparison to DOX, tested extracts were more toxic. Moreover, A. sativum revealed synergistic effect with the drug.
Conclusion: In conclusion, the results indicate the potential application of Allium genus to GC chemoprevention and treatment support through CDH restoration and COX2 downregulation. This issue needs further investigations as it might be used in clinics.
- WHO (2018). Cancer. Available from: https://www.who.int/news-room/fact-sheets/detail/cancer [cited 25 January 2019].
- Nagini S. Carcinoma of the stomach: a review of epidemiology, pathogenesis, molecular genetics and chemoprevention. World J Gastrointest Oncol 2012; 4(7): 156–69. doi: 10.4251/wjgo.v4.i7.156.
- Shi J, Qu JP, Hou P. Pathogenetic mechanisms in gastric cancer. World J Gastroenterol 2014]; 20(38): 13804–19. doi: 10.3748/wjg.v20.i38.13804.
- MacDonald JS, Schein PS, Woolley PV, Smythe T, Ueno W, Hoth D, et al. 5-Fluorouracil, doxorubicin, and mitomycin (FAM) combination chemotherapy for advanced gastric cancer. Ann Intern Med 1980; 93: 533–6. doi: 10.7326/0003-4819-93-4-533.
- Chese MW, Reveal J, Fay MF. A subfamilial classification for the expanded asparagalean families amaryllidaceae, asparagaceae and xanthorrhoeaceae. Bot J Linean Soc 2009; 161: 132–6. doi: 10.1111/j.1095-8339.2009.00999.x.
- Salunkhe VN, Anandhan S, Gawande SJ, Ikkar RB, Bhagat YS, Mahajan V. First report of Colletotrichum truncatum causing anthracnose of mouse garlic (Allium angulosum) in India. Plant Dis 2018; 102(1): 240. doi: 10.1094/PDIS-04-17-0566-PDN
- Pittler MH, Ernst E. Clinical effectiveness of garlic (Allium sativum). Mol Nutr Food Res 2007; 51: 1382–5. doi: 10.1002/mnfr.200700073.
- Stajner D, Igić R, Popović BM, Malencić DJ. Comparative study of antioxidant properties of wild growing and cultivated Allium species. Phytother Res 2008; 22(1): 113–17. doi: https://doi.org/10.1002/ptr.3394.
- Herman-Antosiewicz A, Powolny AA, Singh SV. Molecular targets of cancer chemoprevention by garlic-derived organosulfides. Acta Pharmacol Sin 2007; 28(9): 1355–64 doi: 10.1111/j.1745-7254.2007.00682.x.
- Tsai CW, Chen HW, Sheen LY, Lii CK. Garlic: Health benefits and actions. BioMedicine. Elsevier Taiwan LLC 2012; 2(1): 17–29. doi: 10.1016/j.biomed.2011.12.002.
- Bommareddy A, VanWert AL, McCune DF, Brozena SL, Witczak Z, Singh SV. The role of organosulfur compounds derived from Allium vegetables in cancer prevention and therapy. In: Ullah M, Ahmad A, eds. Critical dietary factors in cancer chemoprevention. Cham: Springer; 2016, pp. 111–52. Available from: https://link.springer.com/chapter/10.1007/978-3-319-21461-0_6 [cited 25 January 2019]. doi: 10.1007/978-3-319-21461-0_6.
- Ristimaki A, Honkanen N, Jankala H, Sipponen P, Harkonen M. Expression of cyclooxygenase-2 in human gastric carcinoma. Cancer Res 1997; 57: 1276–80. Available form: http://cancerres.aacrjournals.org/content/57/7/1276.long [cited 25 January 2019].
- Lim HY, Joo HJ, Choi JH, Yi JW, Yang MS, Cho DY, et al. Increased expression of cyclooxygenase-2 protein in human gastric carcinoma. Clin Cancer Res 2000; 6(2): 519–25. Available from: http://clincancerres.aacrjournals.org/content/6/2/519.long [cited 25 January 2019].
- Mao XY, Wang XG, Lv XJ, Xu L, Han CB. COX-2 expression in gastric cancer and its relationship with angiogenesis using tissue microarray. World J Gastroenterol 2007; 13(25): 3466–71. doi: 10.3748/wjg.v13.i25.3466.
- Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB, et al. Cyclooxygenase in biology and disease. FASEB J 1998; 12: 1063–73. Available from: https://pdfs.semanticscholar.org/4e0d/1583138af91b67a68f7ea55a5d405ce25b1c.pdf [cited 25 January 2019].
- Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998; 93: 705–16. doi: 10.1016/S0092-8674(00)81433-6.
- Dannenberg AJ, Altorki NK, Boyle JO, Dang C, Howe LR, Weksler BB, et al. Cyclooxygenase 2: a pharmacological target for the prevention of cancer. Lancet Oncol 2001; 2: 544–51. doi: 10.1016/S1470-2045(01)00488-0.
- Gumbiner BM. Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev Mol Cell Biol 2005; 6: 622–34. doi: 10.1038/nrm1699.
- Winter JM, Ting AH, Vilardell F, Gallmeier E, Baylin SB, Hruban RH, et al. Absence of E-cadherin expression distinguishes noncohesive from cohesive pancreatic cancer. Clin Cancer Res 2008; 14: 412–18. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810144/ doi: 10.1158/1078-0432.CCR-07-0487 [cited 25 January 2019].
- Dohadwala M, Yang SC, Luo J, Sharma S, Batra RK, Huang M, et al. Cyclooxygenase-2-dependent regulation of E-cadherIn: prostaglandin E(2) induces transcriptional repressors ZEB1 and snail in non-small cell lung cancer. Cancer Res 2006; 66(10): 5338–45. doi: 10.1158/0008-5472.CAN-05-3635.
- Bozzo F, Bassignana A, Lazzarato L, Boschi D, Gasco A, Bocca C, et al. Novel nitro-oxy derivatives of celecoxib for the regulation of colon cancer cell growth. Chem Biol Interact 2009; 182: 183–90. doi: 10.1016/j.cbi.2009.08.006.
- Jang TJ, Cha WH, Lee KS. Reciprocal correlation between the expression of cyclooxygenase-2 and E-cadherin in human bladder transitional cell carcinomas. Virchows Arch 2010; 457: 319–28. doi: 10.1007/s00428-010-0943-3.
- Fujii R, Imanishi Y, Shibata K, Sakai N, Sakamoto K, Shigetomi S, et al. Restoration of E-cadherin expression by selective Cox-2 inhibition and the clinical relevance of the epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma. J Exp Clin Cancer Res 2014; 33: 40. doi: 10.1186/1756-9966-33-40.
- Sitarz R, Leguit RJ, de Leng WW, Morsink FH, Polkowski WP, Maciejewski R, et al. Cyclooxygenase-2 mediated regulation of E-cadherin occurs in conventional but not early-onset gastric cancer cell lines. Cell Oncol 2009; 31: 475–85. doi: 10.3233/CLO-2009-0496.
- Saukkonen K, Rintahaka J, Sivula A, Buskens CJ, Van Rees BP, Rio MC, et al. Cyclooxygenase-2 and gastric carcinogenesis. 2003; APMIS 111: 915–25. doi: 10.1034/j.1600-0463.2003.1111001.x.
- Wang GY, Lu CQ, Zhang RM, Hu XH, Luo ZW. The E-cadherin gene polymorphism −160C→A and cancer risk: a HuGE review and meta-analysis of 26 case-control studies. Am J Epidemiol 2008; 167(1): 7–14. Available from: http://aje.oxfordjournals.org/content/167/1/7.abstract [cited 25 January 2019]. doi: 10.1093/aje/kwm264
- Goldberg Y, Nassif II, Pittas A, Tsai LL, Dynlacht BD, Rigas B, et al. The anti-proliferative effect of sulindac and sulindac sulfide on HT-29 colon cancer cells: alterations in tumor suppressor and cell cycle-regulatory proteins. Oncogene 1996; 12: 893–901.
- Jones MK, Wang H, Peskar BM, Levin E, Itani RM, Sarfeh IJ, et al. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med 1999; 5: 1418–23. Available from: https://www.nature.com/articles/nm1299_1418 [cited 25 January 2019].
- Takahashi T, Kozaki K, Yatabe Y, Achiwa H, Hida T. Increased expression of COX-2 in the development of human lung cancers. J Environ Pathol Toxicol Oncol 2002; 21: 177–81.
- Muller-Decker K, Neufang G, Berger I, Neumann M, Marks F, Furstenberger G. Transgenic cyclooxygenase-2 overexpression sensitizes mouse skin for carcinogenesis. Proc Natl Acad Sci U S A 2002; 99: 12483–8. doi: 10.1073/pnas.192323799.
- Wang Z, Chen J, Liu J. COX-2 inhibitors and gastric cancer. Gastroenterol Res Pract. 2014; 2014: 132320. doi: 10.1155/2014/132320.
- Kim J, Shim M. COX-2 inhibitor NS-398 suppresses doxorubicin-induced p53 accumulation through inhibition of ROS-mediated Jnk activation. Mol Carcinog 2016; 55(12): 2156–67. doi: 10.1002/mc.22458.
- Zeng Y, Li Y, Yang J, Pu X, Du J, Yang X, et al. Therapeutic role of functional components in alliums for preventive chronic disease in human being. Evid Based Complement Alternat Med 2017; 2017: 9402849. doi: 10.1155/2017/9402849.
- Ali M. Mechanism by which garlic (Allium sativum) inhibits cyclooxygenase activity. Effect of raw versus boiled garlic extract on the synthesis of prostanoids. Prostaglandins Leukot Essent Fatty Acids 1995; 53(6): 397–400.
- Segredo MP, Salvadori DM, Rocha NS, Moretto FC, Correa CR, Camargo EA, et al. Oxidative stress on cardiotoxicity after treatment with single and multiple doses of doxorubicin. Hum Exp Toxicol 2014; 33: 748–60. doi: 10.1177/0960327113512342.
- Turati F, Pelucchi C, Guercio V, La Vecchia C, Galeone C. Allium vegetable intake and gastric cancer: a case-control study and meta-analysis. Mol Nutr Food Res 2015; 59(1): 171–9. doi: 10.1002/mnfr.201400496.
- Kodali RT, Eslick GD. Meta-analysis: does garlic intake reduce risk of gastric cancer? Nutr Cancer 2015; 67(1): 1–11. doi: 10.1080/01635581.2015.967873.
- Lamm DL, Riggs DR. The potential application of Allium sativum (garlic) for the treatment of bladder cancer. Urol Clin North Am 2000; 27(1): 157–62,xi. Available from: https://www.sciencedirect.com/science/article/pii/S0094014305702433?via%3Dihub [cited 25 January 2019]. doi: 10.1016/S0094-0143(05)70243-3
- Tafrihi M, Nakhaei Sistani R. E-Cadherin/β-catenin complex: a target for anticancer and antimetastasis plants/plant-derived compounds. Nutr Cancer 2017]; 69(5): 702–22. doi: 10.1080/01635581.2017.1320415.
- Chen HC, Chu RY, Hsu PN, Hsu PI, Lu JY, Lai KH, et al. Loss of E-cadherin expression correlates with poor differentiation and invasion into adjacent organs in gastric adenocarcinomas. Cancer Lett. Ireland. 2003; 201(1): 97–106. doi: 10.1016/j.canlet.2003.07.007.
- Chu Q, Ling MT, Feng H, Cheung HW, Tsao SW, Wang X, et al. A novel anticancer effect of garlic derivatives: inhibition of cancer cell invasion through restoration of E-cadherin expression. Carcinogenesis. England 2006; 27(11): 2180–9. doi: 10.1093/carcin/bgl054
- Tang FY, Chiang EPI, Chung JG, Lee HZ, Hsu CY. S-allylcysteine modulates the expression of E-cadherin and inhibits the malignant progression of human oral cancer. J Nutr Biochem 2009]; 20(12): 1013–20. doi: 10.1016/j.jnutbio.2008.09.007.
- Moden S, Dicarlo SE, Reddy TR. Fresh garlic extract induces growth arrest and morphological differentiation of MCF7 breast cancer cells. Genes Cancer 2012; 3(2): 177–86. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3463925&tool=pmcentrez&rendertype=abstract [cited 25 January 2019]. doi: 10.1177/1947601912458581
- Saukkonen K, Nieminen O, van Rees B, Vilkki S, Härkönen M, Juhola M, et al. Expression of cyclooxygenase-2 in dysplasia of the stomach and in intestinal-type gastric adenocarcinoma. Clin Cancer Res 2001; 7(7): 1923–31. Available from: http://clincancerres.aacrjournals.org/content/7/7/1923.long [cited 25 January 2019].
- Ghazanfari T, Yaraee R, Rahmati B, Hakimzadeh H, Shams J, Jalali-Nadoushan MR. In vitro cytotoxic effect of garlic extract on malignant and nonmalignant cell lines. Immunopharmacol Immunotoxicol 2011; 33(4): 603–8. Available from: http://www.tandfonline.com/doi/full/10.3109/08923973.2011.551832 [cited 25 January 2019]. doi: 10.3109/08923973.2011.551832
- Matsuura N, Miyamae Y, Yamane K, Nagao Y, Hamada Y, Kawaguchi N, et al. Aged garlic extract inhibits angiogenesis and proliferation of colorectal carcinoma cells. J Nutr 2006; 136(3 Suppl): 842S–6S. doi: 10.1093/jn/136.3.842S.
- Chandra-Kuntal K, Lee J, Singh SV. Critical role for reactive oxygen species in apoptosis induction and cell migration inhibition by diallyl trisulfide, a cancer chemopreventive component of garlic. Breast Cancer Res Treat. 2013; 138(1): 69–79. doi: 10.1007/s10549-013-2440-2.
- Xu X, Song G, Yu Y, Ma H, Ma L, Jin Y. Apoptosis and G2/M arrest induced by Allium ursinum (ramson) watery extract in an AGS gastric cancer cell line. Onco Targets Ther 2013; 6: 779–83. doi: 10.2147/OTT.S45865
- Tsubura A, Lai YC, Kuwata M, Uehara N, Yoshizawa K. Anticancer effects of garlic and garlic-derived compounds for breast cancer control. Anticancer Agents Med Chem. 2011; 11(3): 249–53. doi: 10.2174/187152011795347441.
- Tende JA, Ayo JO, Mohammed A, Zezi AU. Blood pressure lowering and cardio-protective effects of garlic (Allium sativum) and ginger (Zingiber officinale) extracts in some laboratory animals. Int J Med Med Sci 2015; 7(1): 8–13. Available from: https://academicjournals.org/journal/IJMMS/article-full-text-pdf/F49ACB050204 [cited 25 January 2015]. doi: 10.5897/IJMMS2014.1069
- Mut-Salud N, Álvarez PJ, Garrido JM, Carrasco E, Aránega A, Rodríguez-Serrano F. Antioxidant intake and antitumor therapy: toward nutritional recommendations for optimal results. Oxid Med Cell Longev 2016; 2016: 6719534. doi: 10.1155/2016/6719534.
- Panchuk R, Skorokhyd N, Chumak V, Lehka L, Omelyanchik S, Gurinovich V, et al. Specific antioxidant compounds differentially modulate cytotoxic activity of doxorubicin and cisplatIn: in vitro and in vivo study. Croat Med J 2014; 55(3): 206–17. doi: 10.3325/cmj.2014.55.206.
Authors retain copyright of their work, with first publication rights granted to SNF Swedish Nutrition Foundation. Read the full Copyright- and Licensing Statement.