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
Oncology Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1021-335X Online ISSN: 1791-2431
Journal Cover
December-2016 Volume 36 Issue 6

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
December-2016 Volume 36 Issue 6

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

Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo

  • Authors:
    • Chi-Hung R. Or
    • Hong-Lin Su
    • Wee-Chyan Lee
    • Shu-Yi Yang
    • Cheesang Ho
    • Chia-Che Chang
  • View Affiliations / Copyright

    Affiliations: Department of Life Science, National Chung Hsing University, Taichung 40227, Taiwan, R.O.C., Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan, R.O.C., Department of Anesthesiology, Kuang Tien General Hospital, Dajia Branch, Taichung 43761, Taiwan, R.O.C.
  • Pages: 3465-3471
    |
    Published online on: October 25, 2016
       https://doi.org/10.3892/or.2016.5201
  • 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

Melanoma is the most aggressive skin malignancy with a high rate of mortality and is frequently refractory to many therapeutics, thus demanding the discovery of novel effective anti-melanoma agents. Diphenhydramine (DPH) is an H1 histamine receptor antagonist and a relatively safe drug. Previous studies have revealed the in vitro cytotoxicity of DPH against melanoma cells, but the mechanisms involved concerning its cytotoxicity and the in vivo anti-melanoma effect remain unknown. We herein present the first evidence supporting that DPH is selectively proapoptotic for a panel of melanoma cell lines irrespective of BRAFV600E status while sparing normal melanocytes. Of note, DPH effectively suppressed tumor growth and prolonged the length of survival of mice bearing B16-F10 melanoma. Mechanistic investigation further revealed that DPH downregulated antiapoptotic MCL-1, whereas MCL-1 overexpression impeded the proapoptotic action of DPH. Moreover, DPH attenuated STAT3 activation, as evidenced by the reduced levels of tyrosine 705-phosphorylated STAT3. Notably, ectopic expression of constitutively active STAT3 mutant reduced DPH-induced apoptosis but also protected MCL-1 from downregulation by DPH, illustrating that DPH impairs STAT3 activation to block STAT3-mediated induction of MCL-1 in eliciting apoptosis. Collectively, we for the first time validate the in vivo anti‑melanoma effect of DPH and also establish DPH as a drug targeting STAT3/MCL-1 survival signaling pathway to induce apoptosis. Our discovery therefore suggests the potential to repurpose DPH as an anti-melanoma therapeutic agent.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Friedman RJ and Heilman ER: The pathology of malignant melanoma. Dermatol Clin. 20:659–676. 2002. View Article : Google Scholar : PubMed/NCBI

2 

Lens MB and Dawes M: Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol. 150:179–185. 2004. View Article : Google Scholar : PubMed/NCBI

3 

Houghton AN and Polsky D: Focus on melanoma. Cancer Cell. 2:275–278. 2002. View Article : Google Scholar : PubMed/NCBI

4 

Diepgen TL and Mahler V: The epidemiology of skin cancer. Br J Dermatol. 146:(Suppl 61). 1–6. 2002. View Article : Google Scholar : PubMed/NCBI

5 

Linos E, Swetter SM, Cockburn MG, Colditz GA and Clarke CA: Increasing burden of melanoma in the United States. J Invest Dermatol. 129:1666–1674. 2009. View Article : Google Scholar : PubMed/NCBI

6 

Antihistamine Drugs, . Drug information. 85. American Society of Hospital Pharmacists; Bethesda, MD: 1985

7 

Dupuis LL and Nathan PC: Optimizing emetic control in children receiving antineoplastic therapy: Beyond the guidelines. Paediatr Drugs. 12:51–61. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Kuo CC, Huang RC and Lou BS: Inhibition of Na+ current by diphenhydramine and other diphenyl compounds: Molecular determinants of selective binding to the inactivated channels. Mol Pharmacol. 57:135–143. 2000.PubMed/NCBI

9 

Green SM, Rothrock SG and Gorchynski J: Validation of diphenhydramine as a dermal local anesthetic. Ann Emerg Med. 23:1284–1289. 1994. View Article : Google Scholar : PubMed/NCBI

10 

Jangi SM, Díaz-Pérez JL, Ochoa-Lizarralde B, Martín-Ruiz I, Asumendi A, Pérez-Yarza G, Gardeazabal J, Díaz-Ramón JL and Boyano MD: H1 histamine receptor antagonists induce genotoxic and caspase-2-dependent apoptosis in human melanoma cells. Carcinogenesis. 27:1787–1796. 2006. View Article : Google Scholar : PubMed/NCBI

11 

Hsieh HY, Shieh JJ, Chen CJ, Pan MY, Yang SY, Lin SC, Chang JS, Lee AYL and Chang CC: Prodigiosin down-regulates SKP2 to induce p27KIP1 stabilization and antiproliferation in human lung adenocarcinoma cells. Br J Pharmacol. 166:2095–2108. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Zhuang L, Lee CS, Scolyer RA, McCarthy SW, Zhang XD, Thompson JF and Hersey P: Mcl-1, Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma. Mod Pathol. 20:416–426. 2007. View Article : Google Scholar : PubMed/NCBI

13 

Perciavalle RM and Opferman JT: Delving deeper: MCL-1s contributions to normal and cancer biology. Trends Cell Biol. 23:22–29. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Belmar J and Fesik SW: Small molecule Mcl-1 inhibitors for the treatment of cancer. Pharmacol Ther. 145:76–84. 2015. View Article : Google Scholar : PubMed/NCBI

15 

Becker TM, Boyd SC, Mijatov B, Gowrishankar K, Snoyman S, Pupo GM, Scolyer RA, Mann GJ, Kefford RF, Zhang XD, et al: Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor. Oncogene. 33:1158–1166. 2014. View Article : Google Scholar : PubMed/NCBI

16 

Niu G, Bowman T, Huang M, Shivers S, Reintgen D, Daud A, Chang A, Kraker A, Jove R and Yu H: Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene. 21:7001–7010. 2002. View Article : Google Scholar : PubMed/NCBI

17 

Siveen KS, Sikka S, Surana R, Dai X, Zhang J, Kumar AP, Tan BKH, Sethi G and Bishayee A: Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors. Biochim Biophys Acta. 1845:136–154. 2014.PubMed/NCBI

18 

Zhao C, Li H, Lin HJ, Yang S, Lin J and Liang G: Feedback activation of STAT3 as a cancer drug-resistance mechanism. Trends Pharmacol Sci. 37:47–61. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Mukherjee N, Lu Y, Almeida A, Lambert K, Shiau CW, Su JC, Luo Y, Fujita M, Robinson WA, Robinson SE, et al: Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells. Oncotarget. Apr 12–2016.(Epub ahead of print).

20 

Jangi SM, Asumendi A, Arlucea J, Nieto N, Perez-Yarza G, Morales MC, de la Fuente-Pinedo M and Boyano MD: Apoptosis of human T-cell acute lymphoblastic leukemia cells by diphenhydramine, an H1 histamine receptor antagonist. Oncol Res. 14:363–372. 2004.PubMed/NCBI

21 

Jangi SM, Ruiz-Larrea MB, Nicolau-Galmés F, Andollo Y, Arroyo-Berdugo N, Ortega-Martínez I, Díaz-Pérez JL and Boyano MD: Terfenadine-induced apoptosis in human melanoma cells is mediated through Ca+2 homeostasis modulation and tyrosine kinase activity, independently of H1 histamine receptors. Carcinogenesis. 29:500–509. 2008. View Article : Google Scholar : PubMed/NCBI

22 

García-Quiroz J and Camacho J: Astemizole: An old anti- histamine as a new promising anti-cancer drug. Anticancer Agents Med Chem. 11:307–314. 2011. View Article : Google Scholar : PubMed/NCBI

23 

Roger S, Gillet L, Le Guennec JY and Besson P: Voltage-gated sodium channels and cancer: Is excitability their primary role? Front Pharmacol. 6:1522015. View Article : Google Scholar : PubMed/NCBI

24 

Fofaria NM, Frederick DT, Sullivan RJ, Flaherty KT and Srivastava SK: Overexpression of Mcl-1 confers resistance to BRAFV600E inhibitors alone and in combination with MEK1/2 inhibitors in melanoma. Oncotarget. 6:40535–40556. 2015.PubMed/NCBI

25 

Liu F, Cao J, Wu J, Sullivan K, Shen J, Ryu B, Xu Z, Wei W and Cui R: Stat3-targeted therapies overcome the acquired resistance to vemurafenib in melanomas. J Invest Dermatol. 133:2041–2049. 2013. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Or CR, Su H, Lee W, Yang S, Ho C and Chang C: Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo. Oncol Rep 36: 3465-3471, 2016.
APA
Or, C.R., Su, H., Lee, W., Yang, S., Ho, C., & Chang, C. (2016). Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo. Oncology Reports, 36, 3465-3471. https://doi.org/10.3892/or.2016.5201
MLA
Or, C. R., Su, H., Lee, W., Yang, S., Ho, C., Chang, C."Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo". Oncology Reports 36.6 (2016): 3465-3471.
Chicago
Or, C. R., Su, H., Lee, W., Yang, S., Ho, C., Chang, C."Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo". Oncology Reports 36, no. 6 (2016): 3465-3471. https://doi.org/10.3892/or.2016.5201
Copy and paste a formatted citation
x
Spandidos Publications style
Or CR, Su H, Lee W, Yang S, Ho C and Chang C: Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo. Oncol Rep 36: 3465-3471, 2016.
APA
Or, C.R., Su, H., Lee, W., Yang, S., Ho, C., & Chang, C. (2016). Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo. Oncology Reports, 36, 3465-3471. https://doi.org/10.3892/or.2016.5201
MLA
Or, C. R., Su, H., Lee, W., Yang, S., Ho, C., Chang, C."Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo". Oncology Reports 36.6 (2016): 3465-3471.
Chicago
Or, C. R., Su, H., Lee, W., Yang, S., Ho, C., Chang, C."Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo". Oncology Reports 36, no. 6 (2016): 3465-3471. https://doi.org/10.3892/or.2016.5201
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