Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Experimental and Therapeutic Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1792-0981 Online ISSN: 1792-1015
Journal Cover
March-2019 Volume 17 Issue 3

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
March-2019 Volume 17 Issue 3

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article Open Access

Novel triazole analogs of apigenin‑7‑methyl ether exhibit potent antitumor activity against ovarian carcinoma cells via the induction of mitochondrial‑mediated apoptosis

  • Authors:
    • Yuyan Qi
    • Zhaoxia Ding
    • Yushuang Yao
    • Dehua Ma
    • Feifei Ren
    • Hongjuan Yang
    • Aiping Chen
  • View Affiliations / Copyright

    Affiliations: Department of Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China, Department of Obstetrics and Gynecology, The Affiliated Hospital of Taishan Medical University, Taian, Shandong 271000, P.R. China
    Copyright: © Qi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1670-1676
    |
    Published online on: December 28, 2018
       https://doi.org/10.3892/etm.2018.7138
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Ovarian cancer is one of the main causes of cancer-associated mortality across the world. Currently, ovarian cancer is mainly treated with chemotherapy. However, ovarian cancer is detected at advanced stages and chemotherapy has numerous side effects. In addition, the results of current chemotherapy on the treatment of ovarian cancer are less than satisfactory. Therefore, there is an urgent need to develop novel and more viable chemotherapeutic agents that can be used to treat ovarian cancer. The present study was designed to synthesize a series of novel triazole analogs of the bioactive apigenin‑7‑methyl ether to evaluate its anticancer activity against three human ovarian cancer cell lines. A total of eight novel triazole derivatives were synthesized and screened for their anticancer activity. Of all the derivatives, a derivative named 3d exhibited significant and dose‑dependent anticancer activity against the SKOV3 ovarian cancer cell line. The IC50 of 3d was found to be 10 µM against the SKOV3 cancer cell line. It was also observed that 3d induced apoptosis in SKOV3 cancer cells through the accretion of reactive oxygen species and reduction in mitochondrial membrane potential. The molecule also modulated the expression of B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein. Taken together, these results showed that the apigenein‑7‑methyl ether novel derivative 3d may prove an important lead molecule for the treatment of ovarian cancer.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

View References

1 

Leary A, Auclin E, Pautier P and Lhommé C: The PI3K/Akt/mTOR pathway in ovarian cancer: Biological rationale and therapeutic opportunities. Ovarian Cancer-A Clinical and Translational Update. 275–302. 2013.

2 

Cancer Genome Atlas Research Network: Integrated genomic analyses of ovarian carcinoma. Nature. 474:609–615. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Altomare DA and Testa JR: Perturbations of the AKT signaling pathway in human cancer. Oncogene. 24:7455–7464. 2005. View Article : Google Scholar : PubMed/NCBI

4 

Engelman JA: Targeting PI3K signalling in cancer: Opportunities, challenges and limitations. Nat Rev Can. 9:550–562. 2009. View Article : Google Scholar

5 

Hafeez BB, Siddiqui IA, Asim M, Malik A, Afaq F, Adhami VM, Saleem M, Din M and Mukhtar H: A dietary anthocyanidin delphinidin induces apoptosis of human prostate cancer PC3 cells in vitro and in vivo: Involvement of nuclear factor-kappa B signaling. Cancer Res. 68:8564–8572. 2008. View Article : Google Scholar : PubMed/NCBI

6 

Hafeez BB, Fischer JW, Singh A, Zhong W, Mustafa A, Meske L, Sheikhani MO and Verma AK: Plumbagin inhibits prostate carcinogenesis in intact and castrated PTEN knockout mice via targeting PKCε, Stat3, and epithelial-to-mesenchymal transition markers. Cancer Prev Res (Phila). 8:375–386. 2015. View Article : Google Scholar : PubMed/NCBI

7 

Lall RK, Adhami VM and Mukhtar H: Dietary flavonoid fisetin for cancer prevention and treatment. Mol Nutr Food Res. 60:1396–1405. 2016. View Article : Google Scholar : PubMed/NCBI

8 

Gülçin I: Antioxidant activity of caffeic acid (3,4-dihydroxycinnamic acid). Toxicology. 217:213–220. 2006. View Article : Google Scholar : PubMed/NCBI

9 

Cook NC and Samman S: Flavonoids-chemistry, metabolism, cardioprotective effects and dietary sources. J NutBiochem. 7:66–76. 1996.

10 

Rice-Evans CA, Miller NJ, Bolwell PG, Bramley PM and Pridham JB: The relative antioxidant activities of plant derived polyphenolic flavonoids. Free Radic Res. 22:375–383. 1995. View Article : Google Scholar : PubMed/NCBI

11 

Kandaswami C, Lee LT, Lee PP, Hwang JJ, Ke FC, Huang YT and Lee MT: The antitumor activities of flavonoids. In vivo. 19:895–909. 2005.PubMed/NCBI

12 

Ren W, Qiao Z, Wang H, Zhu L and Zhang L: Flavonoids: promising anticancer agents. Med Res Rev. 23:519–534. 2003. View Article : Google Scholar : PubMed/NCBI

13 

Ravindranath MH, Muthugounder S, Presser N and Viswanathan S: Anticancer therapeutic potential of soy isoflavone, genistein. Adv Exp Med Biol. 546:121–165. 2004. View Article : Google Scholar : PubMed/NCBI

14 

Wang HK: The therapeutic potential of flavonoids. Expert Opin Investig Drugs. 9:2103–2119. 2000. View Article : Google Scholar : PubMed/NCBI

15 

Nasr Bouzaiene N, Chaabane F, Sassi A, Chekir-Ghedira L and Ghedira K: Effect of apigenin-7-glucoside, genkwanin and naringenin on tyrosinase activity and melanin synthesis in B16F10 melanoma cells. Life Sci. 144:80–85. 2016. View Article : Google Scholar : PubMed/NCBI

16 

Androutsopoulos VP, Ruparelia K, Arroo RR, Tsatsakis AM and Spandidos DA: CYP1-mediated antiproliferative activity of dietary flavonoids in MDA-MB-468 breast cancer cells, Toxicology. 264:162–170. 2009.PubMed/NCBI

17 

Alvarez R, Velázquez S, San-Félix A, Aquaro S, De Clercq E, Perno CF, Karlsson A, Balzarini J and Camarasa MJ: 1,2,3-Triazole-[2′,5′-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3′-spiro-5″-(4″-amino-1″,2″-oxathiole 2″,2″-dioxide) (TSAO) analogues: synthesis and anti-HIV-1 activity. J Med Chem. 37:4185–4194. 1994. View Article : Google Scholar : PubMed/NCBI

18 

Genin MJ, Allwine DA, Anderson DJ, Barbachyn MR, Emmert DE, Garmon SA, Graber DR, Grega KC, Hester JB, Hutchinson DK, et al: Substituent effects on the antibacterial activity of nitrogen-carbon-linked (azolylphenyl)oxazolidinones with expanded activity against the fastidious gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. J Med Chem. 43:953–970. 2000. View Article : Google Scholar : PubMed/NCBI

19 

Majeed R, Sangwan PL, Chinthakindi PK, Khan I, Dangroo NA, Thota N, Hamid A, Sharma PR, Saxena AK and Koul S: Synthesis of 3-O-propargylated betulinic acid and its 1,2,3-triazoles as potential apoptotic agents. Eur J Med Chem. 63:782–792. 2013. View Article : Google Scholar : PubMed/NCBI

20 

Mack DJ, Weinrich ML, Vitaku E and Njarðarson JT: Top 200 Brand Name Drugs by US Retail Sales in 2010. J Chem Ed. 87:13482010.

21 

Waring MJ: Lipophilicity in drug discovery. Expert Opin Drug Discov. 5:235–248. 2010. View Article : Google Scholar : PubMed/NCBI

22 

Lipinski CA, Lombardo F, Dominy BW and Feeney PJ: Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 46:3–26. 2001. View Article : Google Scholar : PubMed/NCBI

23 

Ferreira SB, Sodero AC, Cardoso MF, Lima ES, Kaiser CR, Silva FP and Ferreira VF: Synthesis, biological activity, and molecular modeling studies of 1H-1,2,3-triazole derivatives of carbohydrates as alpha-glucosidases inhibitors. J Med Chem. 53:2364–2375. 2010. View Article : Google Scholar : PubMed/NCBI

24 

Whiting M, Muldoon J, Lin YC, Silverman SM, Lindstrom W, Olson AJ, Kolb HC, Finn MG, Sharpless KB, Elder JH and Fokin VV: Inhibitors of HIV-1 protease by using in situ click chemistry. Angew Chem Int Ed Engl. 45:1435–1439. 2006. View Article : Google Scholar : PubMed/NCBI

25 

Lauria A, Delisi R, Mingoia F, Terenzi A, Martorana A, Barone G and Almerico AM: 1,2,3-Triazole in heterocyclic compounds, endowed with biological activity, through 1,3-dipolar cycloadditions. Eur J Org Chem. 16:3289–3306. 2014. View Article : Google Scholar

26 

Sun SY, Hail N Jr and Lotan R: Apoptosis as a novel target for cancer chemoprevention. J Natl Cancer Inst. 96:662–672. 2004. View Article : Google Scholar : PubMed/NCBI

27 

Chiang JH, Yang JS, Ma CY, Yang MD, Huang HY, Hsia TC, Kuo HM, Wu PP, Lee TH and Chung JG: Danthron, an anthraquinone derivative, induces DNA damage and caspase cascades-mediated apoptosis in SNU-1 human gastric cancer cells through mitochondrial permeability transition pores and Bax-triggered pathways. Chem Res Toxicol. 24:20–29. 2011. View Article : Google Scholar : PubMed/NCBI

28 

Maitra R, Porter MA, Huang S and Gilmour BP: Inhibition of NFkappaB by the natural product Withaferin A in cellular models of Cystic Fibrosis inflammation. J Inflamm (Lond). 6:152009. View Article : Google Scholar : PubMed/NCBI

29 

Hissin PJ and Hilf R: A fluorometric method for determination of oxidized and reduced glutathione in tissues. Anal Biochem. 74:214–226. 1976. View Article : Google Scholar : PubMed/NCBI

30 

Chipuk JE, Bouchier-Hayes L and Green DR: Mitochondrial outer membrane permeabilization during apoptosis: The innocent bystander scenario. Cell Death Differ. 13:1396–1402. 2006. View Article : Google Scholar : PubMed/NCBI

31 

Azuma M, Tamatani T, Ashida Y, Takashima R, Harada K and Sato M: Cisplatin induces apoptosis in oral squamous carcinoma cells by the mitochondria-mediated but not the NF-kappaB-suppressed pathway. Oral Oncol. 39:282–289. 2003. View Article : Google Scholar : PubMed/NCBI

32 

Yoneda K, Yamamoto T and Osaki T: p53- and p21-independent apoptosis of squamous cell carcinoma cells induced by 5-fluorouracil and radiation. Oral Oncol. 34:529–537. 1998. View Article : Google Scholar : PubMed/NCBI

33 

Abal M, Andreu JM and Barasoain I: Taxanes: Microtubule and centrosome targets, and cell cycle dependent mechanisms of action. Curr Canc Drug Targs. 3:193–203. 2003. View Article : Google Scholar

34 

Ferreira CG, Epping M, Kruyt FA and Giaccone G: Apoptosis: Target of cancer therapy. Clin Cancer Res. 8:2024–2034. 2002.PubMed/NCBI

35 

Malaguarnera L: Implications of apoptosis regulators in tumorigenesis. Cancer Met Rev. 23:367–387. 2004. View Article : Google Scholar

36 

Ding H, Han C, Guo D, Chin YW, Ding Y, Kinghorn AD and D'Ambrosio SM: Selective induction of apoptosis of human oral cancer cell lines by avocado extracts via a ROS-mediated mechanism. Nutr Cancer. 61:348–356. 2009. View Article : Google Scholar : PubMed/NCBI

37 

Kowaltowski AJ, de Souza-Pinto NC, Castilho RF and Vercesi AE: Mitochondria and reactive oxygen species. Free Radic Biol Med. 47:333–343. 2009. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Qi Y, Ding Z, Yao Y, Ma D, Ren F, Yang H and Chen A: Novel triazole analogs of apigenin‑7‑methyl ether exhibit potent antitumor activity against ovarian carcinoma cells via the induction of mitochondrial‑mediated apoptosis. Exp Ther Med 17: 1670-1676, 2019.
APA
Qi, Y., Ding, Z., Yao, Y., Ma, D., Ren, F., Yang, H., & Chen, A. (2019). Novel triazole analogs of apigenin‑7‑methyl ether exhibit potent antitumor activity against ovarian carcinoma cells via the induction of mitochondrial‑mediated apoptosis. Experimental and Therapeutic Medicine, 17, 1670-1676. https://doi.org/10.3892/etm.2018.7138
MLA
Qi, Y., Ding, Z., Yao, Y., Ma, D., Ren, F., Yang, H., Chen, A."Novel triazole analogs of apigenin‑7‑methyl ether exhibit potent antitumor activity against ovarian carcinoma cells via the induction of mitochondrial‑mediated apoptosis". Experimental and Therapeutic Medicine 17.3 (2019): 1670-1676.
Chicago
Qi, Y., Ding, Z., Yao, Y., Ma, D., Ren, F., Yang, H., Chen, A."Novel triazole analogs of apigenin‑7‑methyl ether exhibit potent antitumor activity against ovarian carcinoma cells via the induction of mitochondrial‑mediated apoptosis". Experimental and Therapeutic Medicine 17, no. 3 (2019): 1670-1676. https://doi.org/10.3892/etm.2018.7138
Copy and paste a formatted citation
x
Spandidos Publications style
Qi Y, Ding Z, Yao Y, Ma D, Ren F, Yang H and Chen A: Novel triazole analogs of apigenin‑7‑methyl ether exhibit potent antitumor activity against ovarian carcinoma cells via the induction of mitochondrial‑mediated apoptosis. Exp Ther Med 17: 1670-1676, 2019.
APA
Qi, Y., Ding, Z., Yao, Y., Ma, D., Ren, F., Yang, H., & Chen, A. (2019). Novel triazole analogs of apigenin‑7‑methyl ether exhibit potent antitumor activity against ovarian carcinoma cells via the induction of mitochondrial‑mediated apoptosis. Experimental and Therapeutic Medicine, 17, 1670-1676. https://doi.org/10.3892/etm.2018.7138
MLA
Qi, Y., Ding, Z., Yao, Y., Ma, D., Ren, F., Yang, H., Chen, A."Novel triazole analogs of apigenin‑7‑methyl ether exhibit potent antitumor activity against ovarian carcinoma cells via the induction of mitochondrial‑mediated apoptosis". Experimental and Therapeutic Medicine 17.3 (2019): 1670-1676.
Chicago
Qi, Y., Ding, Z., Yao, Y., Ma, D., Ren, F., Yang, H., Chen, A."Novel triazole analogs of apigenin‑7‑methyl ether exhibit potent antitumor activity against ovarian carcinoma cells via the induction of mitochondrial‑mediated apoptosis". Experimental and Therapeutic Medicine 17, no. 3 (2019): 1670-1676. https://doi.org/10.3892/etm.2018.7138
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team