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 Letters
Join Editorial Board Propose a Special Issue
Print ISSN: 1792-1074 Online ISSN: 1792-1082
Journal Cover
July-2018 Volume 16 Issue 1

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
July-2018 Volume 16 Issue 1

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

Anticancer effects of combinational treatment with BRAFV600E siRNA and PI3K pathway inhibitors in melanoma cell lines harboring BRAFV600E

  • Authors:
    • Hongyan He
    • Xiyan Nan
    • Shuang Liu
    • Liangren Zhang
    • Zhenjun Yang
    • Yun Wu
    • Lihe Zhang
  • View Affiliations / Copyright

    Affiliations: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P.R. China
  • Pages: 632-642
    |
    Published online on: May 2, 2018
       https://doi.org/10.3892/ol.2018.8614
  • 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

In the present study, the anti‑tumor effects of combination treatment with an siRNA targeting B‑Raf proto‑oncogene serine/threonine kinase (BRAF)V600E and phosphoinositide 3‑kinase (PI3K) signaling pathway inhibitors was investigated in melanoma cell lines harboring BRAFV600E. Human melanoma A375 and WM115 cells were treated with siRNA targeting to BRAF or BRAFV600E, combined with treatment with PI3K signaling pathway inhibitors. CCK‑8 and EdU proliferation assays were performed to assess cell viability and proliferation, respectively, following treatment. In addition, flow cytometry analysis was performed to determine cell cycle distribution, and western blot analysis was performed to analyze the activity of the extracellular signal‑regulated kinase (ERK) and PI3Ksignaling pathways following treatment. Targeting BRAFV600E using small interfering (si)RNA significantly decreased cell viability and DNA replication in tumor cell lines that harbor oncogenic BRAFV600E. Inhibition of BRAFV600E by siRNA combined with treatment with PI3K or mammalian target of rapamycin signaling pathway inhibitors significantly decreased cell viability and proliferation compared with siRNA or inhibitor treatment alone. Concomitant BRAFV600E and PI3K inhibition led to G1/S phase arrest in melanoma cells. However, melanoma cells in which oncogenic BRAFV600E is not highly expressed (WM115 cells) were not sensitive to BRAFV600E targeted therapy. The PI3K signaling pathway inhibitors were more effective in this cell line. The results from the present study provide an insight into the potential effectiveness of combination therapy and personalized cancer treatments.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

View References

1 

Schadendorf D, Fisher DE, Garbe C, Gershenwald JE, Grob JJ, Halpern A, Herlyn M, Marchetti MA, McArthur G, Ribas A, et al: Melanoma. Nat Rev Disease Primers. 1:150032015. View Article : Google Scholar : PubMed/NCBI

2 

Batus M, Waheed S, Ruby C, Petersen L, Bines SD and Kaufman HL: Optimal management of metastatic melanoma: Current strategies and future directions. Am J Clin Dermatol. 14:179–194. 2013. View Article : Google Scholar : PubMed/NCBI

3 

Gray-Schopfer V, Wellbrock C and Marais R: Melanoma biology and new targeted therapy. Nature. 445:851–857. 2007. View Article : Google Scholar : PubMed/NCBI

4 

Smalley KS, Haass NK, Brafford PA, Lioni M, Flaherty KT and Herlyn M: Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases. Mol Cancer Ther. 5:1136–1144. 2006. View Article : Google Scholar : PubMed/NCBI

5 

Bis S and Tsao H: Melanoma genetics: The other side. Clin Dermatol. 31:148–155. 2013. View Article : Google Scholar : PubMed/NCBI

6 

Rapp UR, Goldsborough MD, Mark GE, Bonner TI, Groffen J, Reynolds FH Jr and Stephenson JR: Structure and biological-activity of v-raf, a unique oncogene transduced by a retrovirus. Proc Natl Acad Sci USA. 80:4218–4222. 1983. View Article : Google Scholar : PubMed/NCBI

7 

Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, et al: Mutations of the BRAF gene in human cancer. Nature. 417:949–954. 2002. View Article : Google Scholar : PubMed/NCBI

8 

Wellbrock C and Hurlstone A: BRAF as therapeutic target in melanoma. Biochem Pharmacol. 80:561–567. 2010. View Article : Google Scholar : PubMed/NCBI

9 

Bucheit AD and Davies MA: Emerging insights into resistance to BRAF inhibitors in melanoma. Biochem Pharmacol. 87:381–389. 2014. View Article : Google Scholar : PubMed/NCBI

10 

Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, et al: Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 468:973–977. 2010. View Article : Google Scholar : PubMed/NCBI

11 

Emery CM, Vijayendran KG, Zipser MC, Sawyer AM, Niu L, Kim JJ, Hatton C, Chopra R, Oberholzer PA, Karpova MB, et al: MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci USA. 106:20411–20416. 2009. View Article : Google Scholar : PubMed/NCBI

12 

Poulikakos PI, Zhang C, Bollag G, Shokat KM and Rosen N: RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 464:427–430. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G, et al: RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 464:431–435. 2010. View Article : Google Scholar : PubMed/NCBI

14 

Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, Hussain J, Reis-Filho JS, Springer CJ, Pritchard C and Marais R: Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 140:209–221. 2010. View Article : Google Scholar : PubMed/NCBI

15 

Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate AJ, Settleman J and Engelman JA: BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal. 3:ra842010. View Article : Google Scholar : PubMed/NCBI

16 

Sharma A, Trivedi NR, Zimmerman MA, Tuveson DA, Smith CD and Robertson GP: Mutant B-V599E-RAF regulates growth and vascular development of malignant melanoma tumors. Cancer Res. 65:2412–2421. 2005. View Article : Google Scholar : PubMed/NCBI

17 

Sánchez-Hernández I, Baquero P, Calleros L and Chiloeches A: Dual inhibition of (V600E)BRAF and the PI3K/AKT/mTOR pathway cooperates to induce apoptosis in melanoma cells through a MEK-independent mechanism. Cancer Lett. 314:244–255. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Fedorenko IV, Gibney GT, Sondak VK and Smalley KS: Beyond BRAF: Where next for melanoma therapy? Br J Cancer. 112:217–226. 2015. View Article : Google Scholar : PubMed/NCBI

19 

Li S, Li Y, Hu R, Li W, Qiu H, Cai H and Wang S: The mTOR inhibitor AZD8055 inhibits proliferation and glycolysis in cervical cancer cells. Oncol Lett. 5:717–721. 2013. View Article : Google Scholar : PubMed/NCBI

20 

Sondak VK, Smalley KS, Kudchadkar R, Grippon S and Kirkpatrick P: Ipilimumab. Nat Rev Drug Discov. 10:411–412. 2011. View Article : Google Scholar : PubMed/NCBI

21 

Mullard A: 2014 FDA drug approvals. Nat Rev Drug Discov. 14:77–81. 2015. View Article : Google Scholar : PubMed/NCBI

22 

Mullard A: 2013 FDA drug approvals. Nat Rev Drug Discov. 13:85–89. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Flaherty KT, Yasothan U and Kirkpatrick P: Vemurafenib. Nat Rev Drug Discov. 10:811–812. 2011. View Article : Google Scholar : PubMed/NCBI

24 

Kim DH and Rossi JJ: Strategies for silencing human disease using RNA interference. Nat Rev Genet. 8:173–184. 2007. View Article : Google Scholar : PubMed/NCBI

25 

Bouchie A: Markets, venture investors and big pharma interest in RNAi soars. Nat Biotechnol. 32:203–204. 2014. View Article : Google Scholar : PubMed/NCBI

26 

Deng Y, Wang CC, Choy KW, Du Q, Chen J, Wang Q, Li L, Chung TK and Tang T: Therapeutic potentials of gene silencing by RNA interference: Principles, challenges, and new strategies. Gene. 538:217–227. 2014. View Article : Google Scholar : PubMed/NCBI

27 

Hingorani SR, Jacobetz MA, Robertson GP, Herlyn M and Tuveson DA: Suppression of BRAF(V599E) in human melanoma abrogates transformation. Cancer Res. 63:5198–5202. 2003.PubMed/NCBI

28 

Sharma A, Tran MA, Liang S, Sharma AK, Amin S, Smith CD, Dong C and Robertson GP: Targeting mitogen-activated protein kinase/extracellular signal-regulated kinase kinase in the mutant (V600E) B-Raf signaling cascade effectively inhibits melanoma lung metastases. Cancer Res. 66:8200–8209. 2006. View Article : Google Scholar : PubMed/NCBI

29 

Posch C, Moslehi H, Feeney L, Green GA, Ebaee A, Feichtenschlager V, Chong K, Peng L, Dimon MT, Phillips T, et al: Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo. Proc Natl Acad Sci USA. 110:4015–4020. 2013. View Article : Google Scholar : PubMed/NCBI

30 

Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, Vincent JP, Ellston R, Jones D, Sini P, et al: AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 70:288–298. 2010. View Article : Google Scholar : PubMed/NCBI

31 

O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, et al: mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66:1500–1508. 2006. View Article : Google Scholar : PubMed/NCBI

32 

Stahl JM, Sharma A, Cheung M, Zimmerman M, Cheng JQ, Bosenberg MW, Kester M, Sandirasegarane L and Robertson GP: Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res. 64:7002–7010. 2004. View Article : Google Scholar : PubMed/NCBI

33 

Shao Y and Aplin AE: Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells. Cancer Res. 70:6670–6681. 2010. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
He H, Nan X, Liu S, Zhang L, Yang Z, Wu Y and Zhang L: Anticancer effects of combinational treatment with BRAFV600E siRNA and PI3K pathway inhibitors in melanoma cell lines harboring BRAFV600E. Oncol Lett 16: 632-642, 2018.
APA
He, H., Nan, X., Liu, S., Zhang, L., Yang, Z., Wu, Y., & Zhang, L. (2018). Anticancer effects of combinational treatment with BRAFV600E siRNA and PI3K pathway inhibitors in melanoma cell lines harboring BRAFV600E. Oncology Letters, 16, 632-642. https://doi.org/10.3892/ol.2018.8614
MLA
He, H., Nan, X., Liu, S., Zhang, L., Yang, Z., Wu, Y., Zhang, L."Anticancer effects of combinational treatment with BRAFV600E siRNA and PI3K pathway inhibitors in melanoma cell lines harboring BRAFV600E". Oncology Letters 16.1 (2018): 632-642.
Chicago
He, H., Nan, X., Liu, S., Zhang, L., Yang, Z., Wu, Y., Zhang, L."Anticancer effects of combinational treatment with BRAFV600E siRNA and PI3K pathway inhibitors in melanoma cell lines harboring BRAFV600E". Oncology Letters 16, no. 1 (2018): 632-642. https://doi.org/10.3892/ol.2018.8614
Copy and paste a formatted citation
x
Spandidos Publications style
He H, Nan X, Liu S, Zhang L, Yang Z, Wu Y and Zhang L: Anticancer effects of combinational treatment with BRAFV600E siRNA and PI3K pathway inhibitors in melanoma cell lines harboring BRAFV600E. Oncol Lett 16: 632-642, 2018.
APA
He, H., Nan, X., Liu, S., Zhang, L., Yang, Z., Wu, Y., & Zhang, L. (2018). Anticancer effects of combinational treatment with BRAFV600E siRNA and PI3K pathway inhibitors in melanoma cell lines harboring BRAFV600E. Oncology Letters, 16, 632-642. https://doi.org/10.3892/ol.2018.8614
MLA
He, H., Nan, X., Liu, S., Zhang, L., Yang, Z., Wu, Y., Zhang, L."Anticancer effects of combinational treatment with BRAFV600E siRNA and PI3K pathway inhibitors in melanoma cell lines harboring BRAFV600E". Oncology Letters 16.1 (2018): 632-642.
Chicago
He, H., Nan, X., Liu, S., Zhang, L., Yang, Z., Wu, Y., Zhang, L."Anticancer effects of combinational treatment with BRAFV600E siRNA and PI3K pathway inhibitors in melanoma cell lines harboring BRAFV600E". Oncology Letters 16, no. 1 (2018): 632-642. https://doi.org/10.3892/ol.2018.8614
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