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
July 2013 Volume 30 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 2013 Volume 30 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

4-Chlorobenzoyl berbamine, a novel berbamine derivative, induces apoptosis in multiple myeloma cells through the IL-6 signal transduction pathway and increases FOXO3a-Bim expression

  • Authors:
    • Jia-Kun Shen
    • Hua-Ping Du
    • Qiuling Ma
    • Min Yang
    • Yun-Gui Wang
    • Jie Jin
  • View Affiliations / Copyright

    Affiliations: Department of Hematology, Institute of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China, Department of Hematology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
  • Pages: 425-432
    |
    Published online on: April 26, 2013
       https://doi.org/10.3892/or.2013.2431
  • 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

Multiple myeloma (MM) is an incurable hematopoietic malignancy, although many novel therapeutic agents have been explored. In the present study, we showed that 4-chlorobenzoyl berbamine (BBD9), a novel derivative of berbamine, inhibited the growth of 4 MM cell lines (U266, RPMI 8226, MM1.R and MM1.S). After a 24‑h treatment with BBD9, the half maximal inhibitory concentration (IC50) values were 1.8, 2.3, 1.5 and 2.4 µg/ml, respectively, using MTT assays. In BBD9-treated U266 and RPMI 8226 cells, Annexin V (AV)-propidium iodide (PI) staining and FACS analysis demonstrated that apoptosis was involved in this inhibition. This was confirmed by western blot analysis indicating activation and cleavage of caspase-3, -8, -9 and PARP. BBD9 also induced G2/M phase cell cycle arrest in these cells. To investigate the mechanisms responsible for BBD9-induced apoptosis, U266 cells were incubated with 0, 1 or 2 µg/ml of BBD9 combined with 0 or 150 ng/ml of interleukin (IL)-6. MTT assays showed that IL-6 partially abrogated the BBD9‑induced cell growth inhibition. Furthermore, BBD9 inhibited autocrine IL-6 production, and downregulated membrane IL‑6 receptor (IL-6R) expression. Crucial proteins downstream of the IL-6 signaling pathway, including AKT and STAT3, were inactivated in BBD9-treated U266 cells, although exogenous IL-6 did not abrogate this effect. Forkhead transcription factor class 3a (FOXO3a), a nuclear transcription factor downstream from AKT, was upregulated in the nuclei of BBD9-treated U266 cells. Bim, the target gene of FOXO3a, was upregulated at both the protein and mRNA levels, as shown by western blot analysis and quantitative PCR. These results suggest that BBD9 induces apoptosis in MM cells through the inhibition of the IL-6 signaling pathway, leading to FOXO3a activation and upregulation of pro-apoptotic Bim.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Barillé-Nion S, Barlogie B, Bataille R, et al: Advances in biology and therapy of multiple myeloma. Hematology Am Soc Hematol Educ Program. 2003:248–278. 2003. View Article : Google Scholar

2 

Kuehl WM and Bergsagel PL: Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer. 2:175–187. 2002. View Article : Google Scholar : PubMed/NCBI

3 

Richardson PG, Mitsiades C, Schlossman R, Munshi N and Anderson K: New drugs for myeloma. Oncologist. 12:664–689. 2007. View Article : Google Scholar : PubMed/NCBI

4 

Lentzsch S, O’Sullivan A, Kennedy RC, et al: Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood. 119:4608–4613. 2012. View Article : Google Scholar

5 

Palumbo A, Attal M and Roussel M: Shifts in the therapeutic paradigm for patients newly diagnosed with multiple myeloma: maintenance therapy and overall survival. Clin Cancer Res. 17:1253–1263. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Lauta VM: A review of the cytokine network in multiple myeloma: diagnostic, prognostic, and therapeutic implications. Cancer. 97:2440–2452. 2003. View Article : Google Scholar : PubMed/NCBI

7 

Trikha M, Corringham R, Klein B and Rossi JF: Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res. 9:4653–4665. 2003.PubMed/NCBI

8 

Hideshima T, Nakamura N, Chauhan D and Anderson KC: Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene. 20:5991–6000. 2001. View Article : Google Scholar : PubMed/NCBI

9 

Ramgolam V, Ang SG, Lai YH, Loh CS and Yap HK: Traditional Chinese medicines as immunosuppressive agents. Ann Acad Med Singapore. 29:11–16. 2000.PubMed/NCBI

10 

Küpeli E, Koşar M, Yeşilada E, Hüsnü K and Başer C: A comparative study on the anti-inflammatory, antinociceptive and antipyretic effects of isoquinoline alkaloids from the roots of Turkish Berberis species. Life Sci. 72:645–657. 2002.PubMed/NCBI

11 

Zhao XY, He ZW, Wu D and Xu RZ: Berbamine selectively induces apoptosis of human acute promyelocytic leukemia cells via survivin-mediated pathway. Chin Med J (Engl). 120:802–806. 2007.PubMed/NCBI

12 

Wang GY, Zhang JW, Lu QH, Xu RZ and Dong QH: Berbamine induces apoptosis in human hepatoma cell line SMMC7721 by loss in mitochondrial transmembrane potential and caspase activation. J Zhejiang Univ Sci B. 8:248–255. 2007. View Article : Google Scholar : PubMed/NCBI

13 

Xu R, Dong Q, Yu Y, et al: Berbamine: a novel inhibitor of bcr/abl fusion gene with potent anti-leukemia activity. Leuk Res. 30:17–23. 2006. View Article : Google Scholar : PubMed/NCBI

14 

Li BY, Fu B, Zhao YL and Li WH: Effects of berbamine on intracellular calcium concentration in cultured HeLa cells. Zhongguo Yao Li Xue Bao. 20:1011–1014. 1999.PubMed/NCBI

15 

Du HP, Shen JK, Yang M, et al: 4-Chlorobenzoyl berbamine induces apoptosis and G2/M cell cycle arrest through the PI3K/Akt and NF-κB signal pathway in lymphoma cells. Oncol Rep. 23:709–716. 2010.PubMed/NCBI

16 

Cui Y, Xu M, Mao J, Ouyang J, Xu R and Yu Y: Synthesis of berbamine acetyl glycosides and evaluation of antitumor activity. Eur J Med Chem. 54:867–872. 2012. View Article : Google Scholar : PubMed/NCBI

17 

Vermes I, Haanen C, Steffens-Nakken H and Reutelingsperger C: A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J Immunol Methods. 184:39–51. 1995. View Article : Google Scholar

18 

Dorée M and Hunt T: From Cdc2 to Cdk1: when did the cell cycle kinase join its cyclin partner? J Cell Sci. 115:2461–2464. 2002.PubMed/NCBI

19 

Galea CA, Wang Y, Sivakolundu SG and Kriwacki RW: Regulation of cell division by intrinsically unstructured proteins: intrinsic flexibility, modularity, and signaling conduits. Biochemistry. 47:7598–7609. 2008. View Article : Google Scholar : PubMed/NCBI

20 

Toyoshima-Morimoto F, Taniguchi E, Shinya N, Iwamatsu A and Nishida E: Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase. Nature. 410:215–220. 2001. View Article : Google Scholar : PubMed/NCBI

21 

Klein B, Zhang XG, Lu ZY and Bataille R: Interleukin-6 in human multiple myeloma. Blood. 85:863–872. 1995.PubMed/NCBI

22 

Kovacs E: Multiple myeloma and B cell lymphoma. Investigation of IL-6, IL-6 receptor antagonist (IL-6RA), and GP130 antagonist (GP130A) using various parameters in an in vitro model. Sc World J. 6:888–898. 2006. View Article : Google Scholar

23 

Guo Y, Xu F, Lu T, Duan Z and Zhang Z: Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev. 38:904–910. 2012. View Article : Google Scholar : PubMed/NCBI

24 

Petros AM, Olejniczak ET and Fesik SW: Structural biology of the Bcl-2 family of proteins. Biochim Biophys Acta. 1644:83–94. 2004. View Article : Google Scholar : PubMed/NCBI

25 

Willis SN, Fletcher JI, Kaufmann T, et al: Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science. 315:856–859. 2007. View Article : Google Scholar : PubMed/NCBI

26 

Hübner A, Barrett T, Flavell RA and Davis RJ: Multisite phosphorylation regulates Bim stability and apoptotic activity. Mol Cell. 30:415–425. 2008.PubMed/NCBI

27 

Brunet A, Bonni A, Zigmond MJ, et al: Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 96:857–868. 1999. View Article : Google Scholar : PubMed/NCBI

28 

Barreyro FJ, Kobayashi S, Bronk SF, Werneburg NW, Malhi H and Gores GJ: Transcriptional regulation of Bim by FoxO3A mediates hepatocyte lipoapoptosis. J Biol Chem. 282:27141–27154. 2007. View Article : Google Scholar : PubMed/NCBI

29 

Modur V, Nagarajan R, Evers BM and Milbrandt J: FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. J Biol Chem. 277:47928–47937. 2002. View Article : Google Scholar

30 

Burgering BM and Kops GJ: Cell cycle and death control: long live Forkheads. Trends Biochem Sci. 27:352–360. 2002. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Shen J, Du H, Ma Q, Yang M, Wang Y and Jin J: 4-Chlorobenzoyl berbamine, a novel berbamine derivative, induces apoptosis in multiple myeloma cells through the IL-6 signal transduction pathway and increases FOXO3a-Bim expression. Oncol Rep 30: 425-432, 2013.
APA
Shen, J., Du, H., Ma, Q., Yang, M., Wang, Y., & Jin, J. (2013). 4-Chlorobenzoyl berbamine, a novel berbamine derivative, induces apoptosis in multiple myeloma cells through the IL-6 signal transduction pathway and increases FOXO3a-Bim expression. Oncology Reports, 30, 425-432. https://doi.org/10.3892/or.2013.2431
MLA
Shen, J., Du, H., Ma, Q., Yang, M., Wang, Y., Jin, J."4-Chlorobenzoyl berbamine, a novel berbamine derivative, induces apoptosis in multiple myeloma cells through the IL-6 signal transduction pathway and increases FOXO3a-Bim expression". Oncology Reports 30.1 (2013): 425-432.
Chicago
Shen, J., Du, H., Ma, Q., Yang, M., Wang, Y., Jin, J."4-Chlorobenzoyl berbamine, a novel berbamine derivative, induces apoptosis in multiple myeloma cells through the IL-6 signal transduction pathway and increases FOXO3a-Bim expression". Oncology Reports 30, no. 1 (2013): 425-432. https://doi.org/10.3892/or.2013.2431
Copy and paste a formatted citation
x
Spandidos Publications style
Shen J, Du H, Ma Q, Yang M, Wang Y and Jin J: 4-Chlorobenzoyl berbamine, a novel berbamine derivative, induces apoptosis in multiple myeloma cells through the IL-6 signal transduction pathway and increases FOXO3a-Bim expression. Oncol Rep 30: 425-432, 2013.
APA
Shen, J., Du, H., Ma, Q., Yang, M., Wang, Y., & Jin, J. (2013). 4-Chlorobenzoyl berbamine, a novel berbamine derivative, induces apoptosis in multiple myeloma cells through the IL-6 signal transduction pathway and increases FOXO3a-Bim expression. Oncology Reports, 30, 425-432. https://doi.org/10.3892/or.2013.2431
MLA
Shen, J., Du, H., Ma, Q., Yang, M., Wang, Y., Jin, J."4-Chlorobenzoyl berbamine, a novel berbamine derivative, induces apoptosis in multiple myeloma cells through the IL-6 signal transduction pathway and increases FOXO3a-Bim expression". Oncology Reports 30.1 (2013): 425-432.
Chicago
Shen, J., Du, H., Ma, Q., Yang, M., Wang, Y., Jin, J."4-Chlorobenzoyl berbamine, a novel berbamine derivative, induces apoptosis in multiple myeloma cells through the IL-6 signal transduction pathway and increases FOXO3a-Bim expression". Oncology Reports 30, no. 1 (2013): 425-432. https://doi.org/10.3892/or.2013.2431
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