Download PDF
Drug Res (Stuttg) 2021; 71(08): 448-454
DOI: 10.1055/a-1525-1499
Original Article

Allicin Reduces 5-fluorouracil-resistance in Gastric Cancer Cells through Modulating MDR1, DKK1, and WNT5A Expression

Parya Khakbaz 
1   Student Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
2   Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
,
Reza Panahizadeh 
1   Student Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
2   Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
,
Mohammad Amin Vatankhah 
1   Student Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
2   Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
,
Nowruz Najafzadeh 
2   Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
› Author Affiliations
› Further Information
Also available at
   Permissions and Reprints

Abstract

Background & Objective 5-fluorouracil (5-FU) is approved for the treatment of gastric carcinoma (GC), but chemo-resistance limits the application of it for GC. Thus, the combination of 5-FU with adjuvants such as allicin may overcome multidrug resistance (MDR).

Methods The anticancer effects of allicin, 5-FU, and allicin/5-FU on the 5-FU resistant MKN-45 cells were evaluated by MTT assay and DAPi staining. The expression of the P-glycoprotein (P-gp) and CD44 protein were determined using immunocytochemistry. We also quantified mRNA expression levels of WNT5A, Dickkopf-1 (DKK1), and MDR1 in the GC cells.

Results Here, we found that the combination of allicin with 5-FU significantly increased apoptosis compared to 5-FU alone (P<0.05). We showed that WNT5A, MDR1, and DKK1 mRNA expression levels were down-regulated in the allicin- and allicin/5-FU-treated cells. Indeed, the combination of allicin and 5-FU significantly decreased the expression of the P-gp and CD44 proteins (P<0.05).

Conclusion Our findings indicate that the combination of allicin with 5-FU could reverse multidrug resistance in the GC cells by reducing the expression of WNT5A, DKK1, MDR1, P-gp, and CD44 levels.

Key words

Gastric cancer - chemoresistance - allicin - 5-fluorouracil - CD44 - P-glycoprotein


Publication History

Article published online:
14 July 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Bray F, Ferlay J, Soerjomataram I. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394-424 DOI: 10.3322/caac.21492..
    CrossrefPubMedGoogle Scholar
  • 2 Fitzmaurice C, Akinyemiju TF, Al Lami FH. et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: A systematic analysis for the global burden of disease study. JAMA oncology 2018; 4: 1553-1568
    CrossrefPubMedGoogle Scholar
  • 3 Van Cutsem E, Sagaert X, Topal B. et al. Gastric cancer. The Lancet 2016; 388: 2654-2664
    CrossrefPubMedGoogle Scholar
  • 4 Van Cutsem E, Moiseyenko VM, Tjulandin S. et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: A report of the V325 Study Group. J Clin Oncol 2006; 24: 4991-4997
    CrossrefPubMedGoogle Scholar
  • 5 Shi W-J, Gao J-B. Molecular mechanisms of chemoresistance in gastric cancer. World J Gastrointest Oncol 2016; 8: 673-681. DOI: 10.4251/wjgo.v8.i9.673.
    CrossrefPubMedGoogle Scholar
  • 6 Mansoori B, Mohammadi A, Davudian S. et al. The different mechanisms of cancer drug resistance: A brief review. Advanced Pharmaceutical Bulletin 2017; 7: 339
    CrossrefPubMedGoogle Scholar
  • 7 Wei W, Sun HH, Li N. et al. WNT5A modulates cell cycle progression and contributes to the chemoresistance in pancreatic cancer cells. Hepatobiliary & Pancreatic Diseases International : HBPD INT 2014; 13: 529-538. DOI: 10.1016/s1499-3872(14)60277-0.
    CrossrefPubMedGoogle Scholar
  • 8 Aguilera Ó, González-Sancho JM, Zazo S. et al. Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer. Oncotarget 2015; 6: 5903
    CrossrefPubMedGoogle Scholar
  • 9 Demaria M, O'Leary MN, Chang J. et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discovery 2017; 7: 165-176
    CrossrefPubMedGoogle Scholar
  • 10 Jiang W, Huang Y, Wang J-P. et al. The synergistic anticancer effect of artesunate combined with allicin in osteosarcoma cell line in vitro and in vivo. Asian Pacific Journal of Cancer Prevention 2013; 14: 4615-4619
    CrossrefPubMedGoogle Scholar
  • 11 Gao X-Y, Geng X-J, Zhai W-L. et al. Effect of combined treatment with cyclophosphamidum and allicin on neuroblastoma–bearing mice. Asian Pac J Trop Med 2015; 8: 137-141
    CrossrefPubMedGoogle Scholar
  • 12 Mohammadi Jobani B, Najafzadeh N, Mazani M. et al. Molecular mechanism and cytotoxicity of allicin and all-trans retinoic acid against CD44+versus CD117+melanoma cells. Phytomedicine 2018; 48: 161-169
    CrossrefPubMedGoogle Scholar
  • 13 Ţigu AB, Toma V-A, Moţ AC. et al. The Synergistic Antitumor Effect of 5-Fluorouracil Combined with Allicin against Lung and Colorectal Carcinoma Cells. Molecules 2020; 25: 1947
    CrossrefPubMedGoogle Scholar
  • 14 Zhang W, Ha M, Gong Y. et al. Allicin induces apoptosis in gastric cancer cells through activation of both extrinsic and intrinsic pathways. Oncology Reports 2010; 24: 1585-1592
    PubMedGoogle Scholar
  • 15 Zou X, Liang J, Sun J. et al. Allicin sensitizes hepatocellular cancer cells to anti-tumor activity of 5-fluorouracil through ROS-mediated mitochondrial pathway. Journal of Pharmacological Sciences 2016; 131: 233-240
    CrossrefPubMedGoogle Scholar
  • 16 Pouremamali F, Jeddi F, Samadi N. Nrf2-ME-1 axis is associated with 5-FU resistance in gastric cancer cell line. Process Biochemistry. 2020
    Google Scholar
  • 17 Mokabber H, Najafzadeh N, Mohammadzadeh Vardin M. miR-124 promotes neural differentiation in mouse bulge stem cells by repressing Ptbp1 and Sox9. J Cell Physiol 2019; 234: 8941-8950 DOI: 10.1002/jcp.27563.
    CrossrefPubMedGoogle Scholar
  • 18 Fatehi-Agdam M, Vatankhah MA, Panahizadeh R. et al. Efficacy of Metformin and Chemotherapeutic Agents on the Inhibition of Colony Formation and Shh/Gli1 Pathway: Metformin/Docetaxel Versus Metformin/5-Fluorouracil. Drug Research 2021; 71: 17-25
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Mohammadi Jobani B, Mohebi E, Najafzadeh N. In Vitro Anticancer Effects of All-trans Retinoic Acid in Combination with Dacarbazine against CD117+Melanoma Cells. Drug Research 2020; 70: 563-569
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Jiang W, Huang Y, Wang J-P. et al. The synergistic anticancer effect of artesunate combined with allicin in osteosarcoma cell line in vitro and in vivo. Asian Pac J Cancer Prev 2013; 14: 4615-4619
    CrossrefPubMedGoogle Scholar
  • 21 Sarkhani E, Najafzadeh N, Tata N. et al. Molecular mechanisms of methylsulfonylmethane and allicin in the inhibition of CD44±breast cancer cells growth. Journal of functional foods 2017; 39: 50-57
    CrossrefPubMedGoogle Scholar
  • 22 Wright MH, Calcagno AM, Salcido CD. et al. Brca1 breast tumors contain distinct CD44+/CD24-and CD133+cells with cancer stem cell characteristics. Breast Cancer Research 2008; 10: R10
    CrossrefPubMedGoogle Scholar
  • 23 Shen DY, Zhang W, Zeng X. et al. Inhibition of Wnt/β-catenin signaling downregulates P-glycoprotein and reverses multi-drug resistance of cholangiocarcinoma. Cancer Science 2013; 104: 1303-1308
    CrossrefPubMedGoogle Scholar
  • 24 Chung HC, Gong SJ, Yoo NC. et al. P-glycoprotein as an intermediate end point of drug resistance to neoadjuvant chemotherapy in locally advanced gastric cancer. Yonsei Medical Journal 1996; 37: 397-404
    CrossrefPubMedGoogle Scholar
  • 25 Cha JH, Choi YJ, Cha SH. et al. Allicin inhibits cell growth and induces apoptosis in U87MG human glioblastoma cells through an ERK-dependent pathway. Oncology Reports 2012; 28: 41-48
    PubMedGoogle Scholar
  • 26 Wang Z, Xia Q, Cui J. et al. Reversion of P-glycoprotein-mediated multidrug resistance by diallyl trisulfide in a human osteosarcoma cell line. Oncology Reports 2014; 31: 2720-2726
    CrossrefPubMedGoogle Scholar
  • 27 Arora A, Seth K, Shukla Y. Reversal of P-glycoprotein-mediated multidrug resistance by diallyl sulfide in K562 leukemic cells and in mouse liver. Carcinogenesis 2004; 25: 941-949. DOI: 10.1093/carcin/bgh060.
    CrossrefPubMedGoogle Scholar
  • 28 Jeong YS, Lam TG, Jeong S. et al. Metformin Derivative HL156A Reverses Multidrug Resistance by Inhibiting HOXC6/ERK1/2 Signaling in Multidrug-Resistant Human Cancer Cells. Pharmaceuticals 2020; 13: 218
    CrossrefPubMedGoogle Scholar
  • 29 Astudillo P. Wnt5a signaling in gastric cancer. Frontiers in Cell and Developmental Biology 2020; 8: 110
    CrossrefPubMedGoogle Scholar
  • 30 Hong SA, Yoo SH, Lee HH. et al. Prognostic value of Dickkopf-1 and ss-catenin expression in advanced gastric cancer. BMC Cancer 2018; 18: 506
    CrossrefPubMedGoogle Scholar
  • 31 Xu Y-s, Feng J-g, Zhang D. et al. S-allylcysteine, a garlic derivative, suppresses proliferation and induces apoptosis in human ovarian cancer cells in vitro. Acta Pharmacologica Sinica 2014; 35: 267-274
    CrossrefPubMedGoogle Scholar
  • 32 Wang B, Liu J, Ma LN. et al. Chimeric 5/35 adenovirus-mediated Dickkopf-1 overexpression suppressed tumorigenicity of CD44+gastric cancer cells via attenuating Wnt signaling. Journal of Gastroenterology 2013; 48: 798-808
    CrossrefPubMedGoogle Scholar
  • 33 Lee HS, Lee HE, Park DJ. et al. Clinical significance of serum and tissue Dickkopf-1 levels in patients with gastric cancer. Clinica Chimica Acta 2012; 413: 1753-1760
    CrossrefPubMedGoogle Scholar
  • 34 Xiao J, Xing F, Liu Y. et al. Garlic-derived compound S-allylmercaptocysteine inhibits hepatocarcinogenesis through targeting LRP6/Wnt pathway. Acta Pharmaceutica Sinica B 2018; 8: 575-586
    CrossrefPubMedGoogle Scholar