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
International Journal of Oncology
Join Editorial Board Propose a Special Issue
Print ISSN: 1019-6439 Online ISSN: 1791-2423
Journal Cover
August-2018 Volume 53 Issue 2

Full Size Image

Cover Legend PDF

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
August-2018 Volume 53 Issue 2

Full Size Image

Cover Legend PDF

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

Diosmetin suppresses human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest

  • Authors:
    • Christine Oak
    • Ahmad O. Khalifa
    • Ilaha Isali
    • Natarajan Bhaskaran
    • Ethan Walker
    • Sanjeev Shukla
  • View Affiliations / Copyright

    Affiliations: Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
  • Pages: 835-843
    |
    Published online on: May 16, 2018
       https://doi.org/10.3892/ijo.2018.4407
  • 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

Diosmetin, a plant flavonoid, has been shown to exert promising effects on prostate cancer cells as an anti‑proliferative and anticancer agent. In this study, using western blot analysis for protein expression and flow cytometry for cell cycle analysis, we determined that the treatment of the LNCaP and PC‑3 prostate cancer cells with diosmetin resulted in a marked decrease in cyclin D1, Cdk2 and Cdk4 expression levels (these proteins remain active in the G0‑G1 phases of the cell cycle). These changes were accompanied by a decrease in c-Myc and Bcl-2 expression, and by an increase in Bax, p27Kip1 and FOXO3a protein expression, which suggests the potential modulatory effects of diosmetin on protein transcription. The treatment of prostate cancer cells with diosmetin set in motion an apoptotic machinery by inhibiting X-linked inhibitor of apoptosis (XIAP) and increasing cleaved PARP and cleaved caspase-3 expression levels. On the whole, the findings of this study provide an in-depth analysis of the molecular mechanisms responsible for the regulatory effects of diosmetin on key molecules that perturb the cell cycle to inhibit cell growth, and suggest that diosmetin may prove to be an effective anticancer agent for use in the treatment of prostate cancer in the future.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

View References

1 

Asghar U, Witkiewicz AK, Turner NC and Knudsen ES: The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 14:130–146. 2015. View Article : Google Scholar

2 

Mateyak MK, Obaya AJ and Sedivy JM: c-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle progression at multiple independent points. Mol Cell Biol. 19:4672–4683. 1999. View Article : Google Scholar

3 

Prall OW, Sarcevic B, Musgrove EA, Watts CK and Sutherland RL: Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J Biol Chem. 272:10882–10894. 1997. View Article : Google Scholar

4 

Pei XH and Xiong Y: Biochemical and cellular mechanisms of mammalian CDK inhibitors: A few unresolved issues. Oncogene. 24:2787–2795. 2005. View Article : Google Scholar

5 

Shapiro GI: Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 24:1770–1783. 2006. View Article : Google Scholar

6 

Benson C, Kaye S, Workman P, Garrett M, Walton M and de Bono J: Clinical anticancer drug development: Targeting the cyclin-dependent kinases. Br J Cancer. 92:7–12. 2005. View Article : Google Scholar

7 

Sausville EA: Complexities in the development of cyclin-dependent kinase inhibitor drugs. Trends Mol Med. 8(Suppl 4): S32–S37. 2002. View Article : Google Scholar

8 

Androutsopoulos V, Wilsher N, Arroo RR and Potter GA: Bioactivation of the phytoestrogen diosmetin by CYP1 cytochromes 450. Cancer Lett. 274:54–60. 2009. View Article : Google Scholar

9 

Liu B, Jia K, Yang Y, Hao S, Lu C, Xu F, Feng D and Zhu R: Diosmetin induces cell apoptosis by regulating CYP1A1/CYP1A2 due to 53 activation in HepG2 cells. Protein Pept Lett. 24:406–412. 2017. View Article : Google Scholar

10 

Xu Z, Yan Y, Xiao L, Dai S, Zeng S, Qian L, Wang L, Yang X, Xiao Y and Gong Z: Radiosensitizing effect of diosmetin on radioresistant lung cancer cells via Akt signaling pathway. PLoS One. 12:e01759772017. View Article : Google Scholar

11 

Androutsopoulos VP, Mahale S, Arroo RR and Potter G: Anticancer effects of the flavonoid diosmetin on cell cycle progression and proliferation of MDA-MB 468 breast cancer cells due to CYP1 activation. Oncol Rep. 21:1525–1528. 2009.

12 

Liu J, Ren H, Liu B, Zhang Q, Li M and Zhu R: Diosmetin inhibits cell proliferation and induces apoptosis by regulating autophagy via the mammalian target of rapamycin pathway in hepatocellular carcinoma HepG2 cells. Oncol Lett. 12:4385–4392. 2016. View Article : Google Scholar

13 

Barrajón-Catalán E, Taamalli A, Quirantes-Piné R, Roldan-Segura C, Arráez-Román D, Segura-Carretero A, Micol V and Zarrouk M: Differential metabolomic analysis of the potential antiproliferative mechanism of olive leaf extract on the JIMT-1 breast cancer cell line. J Pharm Biomed Anal. 105:156–162. 2015. View Article : Google Scholar

14 

Ciolino HP, Dankwah M and Yeh GC: Resistance of MCF-7 cells to dimethylbenz(a)anthracene-induced apoptosis is due to reduced CYP1A1 expression. Int J Oncol21:. 385–391. 2002.

15 

Roma A, Rota SG and Spagnuolo PA: Diosmetin induces apoptosis of acute myeloid leukemia cells. Mol Pharm. 15:1353–1360. 2018. View Article : Google Scholar

16 

Androutsopoulos VP and Spandidos DA: The flavonoids diosmetin and luteolin exert synergistic cytostatic effects in human hepatoma HepG2 cells via CYP1A-catalyzed metabolism, activation of JNK and ERK and P53/P21 up-regulation. J Nutr Biochem. 24:496–504. 2013. View Article : Google Scholar

17 

Pozarowski P and Darzynkiewicz Z: Analysis of cell cycle by flow cytometry. Methods Mol Biol. 281:301–311. 2004.

18 

Hawksworth D, Ravindranath L, Chen Y, Furusato B, Sesterhenn IA, McLeod DG, Srivastava S and Petrovics G: Overexpression of C-MYC oncogene in prostate cancer predicts biochemical recurrence. Prostate Cancer Prostatic Dis. 13:311–315. 2010. View Article : Google Scholar

19 

Chandramohan V, Mineva ND, Burke B, Jeay S, Wu M, Shen J, Yang W, Hann SR and Sonenshein GE: c-Myc represses FOXO3a-mediated transcription of the gene encoding the p27(Kip1) cyclin dependent kinase inhibitor. J Cell Biochem. 104:2091–2106. 2008. View Article : Google Scholar

20 

Ferro M, Terracciano D, Buonerba C, Lucarelli G, Bottero D, Perdonà S, Autorino R, Serino A, Cantiello F and Damiano R: The emerging role of obesity, diet and lipid metabolism in prostate cancer. Future Oncol. 13:285–293. 2017. View Article : Google Scholar

21 

de Cobelli O, Terracciano D, Tagliabue E, Raimondi S, Galasso G, Cioffi A, Cordima G, Musi G, Damiano R, Cantiello F, et al: Body mass index was associated with upstaging and upgrading in patients with low-risk prostate cancer who met the inclusion criteria for active surveillance. Urol Oncol. 33:201.e1–201.e8. 2015. View Article : Google Scholar

22 

Barbieri A, Bimonte S, Palma G, Luciano A, Rea D, Giudice A, Scognamiglio G, La Mantia E, Franco R and Perdonà S: The stress hormone norepinephrine increases migration of prostate cancer cells in vitro an in vivo. Int J Oncol. 47:527–534. 2015. View Article : Google Scholar

23 

Patel R, Khalifa AO, Isali I and Shukla S: Prostate cancer susceptibility and growth linked to Y chromosome genes. Front Biosci (Elite Ed). 10:423–436. 2018.

24 

Dickson MA and Schwartz GK: Development of cell-cycle inhibitors for cancer therapy. Curr Oncol. 16:36–43. 2009.

25 

Sandal T: Molecular aspects of the mammalian cell cycle and cancer. Oncologist. 7:73–81. 2002. View Article : Google Scholar

26 

Malumbres M: Cyclin-dependent kinases. Genome Biol. 15:1222014. View Article : Google Scholar

27 

Dong P, Maddali MV, Srimani JK, Thélot F, Nevins JR, Mathey-Prevot B and You L: Division of labour between Myc and G1 cyclins in cell cycle commitment and pace control. Nat Commun. 5:47502014. View Article : Google Scholar

28 

Peck B, Ferber EC and Schulze A: Antagonism between FOXO and MYC regulates cellular powerhouse. Front Oncol. 3:962013. View Article : Google Scholar

29 

Tarrado-Castellarnau M, de Atauri P and Cascante M: Oncogenic regulation of tumor metabolic reprogramming. Oncotarget. 7:62726–62753. 2016. View Article : Google Scholar

30 

Eijkelenboom A, Mokry M, de Wit E, Smits LM, Polderman PE, van Triest MH, van Boxtel R, Schulze A, de Laat W and Cuppen E: Genome-wide analysis of FOXO3 mediated transcription regulation through RNA polymerase II profiling. Mol Syst Biol. 9:6382013. View Article : Google Scholar

31 

Ferber EC, Peck B, Delpuech O, Bell GP, East P and Schulze A: FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression. Cell Death Differ. 19:968–979. 2012. View Article : Google Scholar

32 

Alao JP: The regulation of cyclin D1 degradation: Roles in cancer development and the potential for therapeutic invention. Mol Cancer. 6:242007. View Article : Google Scholar

33 

Mueller A, Odze R, Jenkins TD, Shahsesfaei A, Nakagawa H, Inomoto T and Rustgi AK: A transgenic mouse model with cyclin D1 overexpression results in cell cycle, epidermal growth factor receptor, and p53 abnormalities. Cancer Res. 57:5542–5549. 1997.

34 

Besson A, Dowdy SF and Roberts JM: CDK inhibitors: Cell cycle regulators and beyond. Dev Cell. 14:159–169. 2008. View Article : Google Scholar

35 

Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL and Korsmeyer SJ: Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 75:241–251. 1993. View Article : Google Scholar

36 

Kelly PN and Strasser A: The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapy. Cell Death Differ. 18:1414–1424. 2011. View Article : Google Scholar

37 

Cova D, De Angelis L, Giavarini F, Palladini G and Perego R: Pharmacokinetics and metabolism of oral diosmin in healthy volunteers. Int J Clin Pharmacol Ther Toxicol. 30:29–33. 1992.

38 

Spanakis M, Kasmas S and Niopas I: Simultaneous determination of the flavonoid aglycones diosmetin and hesperetin in human plasma and urine by a validated GC/MS method: In vivo metabolic reduction of diosmetin to hesperetin. Biomed Chromatogr. 23:124–131. 2009. View Article : Google Scholar

39 

Silvestro L, Tarcomnicu I, Dulea C, Attili NR, Ciuca V, Peru D and Rizea Savu S: Confirmation of diosmetin 3-O-glucuronide as major metabolite of diosmin in humans, using micro-liquid-chromatography-mass spectrometry and ion mobility mass spectrometry. Anal Bioanal Chem. 405:8295–8310. 2013. View Article : Google Scholar

40 

Quintieri L, Palatini P, Moro S and Floreani M: Inhibition of cytochrome P450 2C8-mediated drug metabolism by the flavonoid diosmetin. Drug Metab Pharmacokinet. 26:559–568. 2011. View Article : Google Scholar

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Oak C, Khalifa AO, Isali I, Bhaskaran N, Walker E and Shukla S: Diosmetin suppresses human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest. Int J Oncol 53: 835-843, 2018.
APA
Oak, C., Khalifa, A.O., Isali, I., Bhaskaran, N., Walker, E., & Shukla, S. (2018). Diosmetin suppresses human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest. International Journal of Oncology, 53, 835-843. https://doi.org/10.3892/ijo.2018.4407
MLA
Oak, C., Khalifa, A. O., Isali, I., Bhaskaran, N., Walker, E., Shukla, S."Diosmetin suppresses human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest". International Journal of Oncology 53.2 (2018): 835-843.
Chicago
Oak, C., Khalifa, A. O., Isali, I., Bhaskaran, N., Walker, E., Shukla, S."Diosmetin suppresses human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest". International Journal of Oncology 53, no. 2 (2018): 835-843. https://doi.org/10.3892/ijo.2018.4407
Copy and paste a formatted citation
x
Spandidos Publications style
Oak C, Khalifa AO, Isali I, Bhaskaran N, Walker E and Shukla S: Diosmetin suppresses human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest. Int J Oncol 53: 835-843, 2018.
APA
Oak, C., Khalifa, A.O., Isali, I., Bhaskaran, N., Walker, E., & Shukla, S. (2018). Diosmetin suppresses human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest. International Journal of Oncology, 53, 835-843. https://doi.org/10.3892/ijo.2018.4407
MLA
Oak, C., Khalifa, A. O., Isali, I., Bhaskaran, N., Walker, E., Shukla, S."Diosmetin suppresses human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest". International Journal of Oncology 53.2 (2018): 835-843.
Chicago
Oak, C., Khalifa, A. O., Isali, I., Bhaskaran, N., Walker, E., Shukla, S."Diosmetin suppresses human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest". International Journal of Oncology 53, no. 2 (2018): 835-843. https://doi.org/10.3892/ijo.2018.4407
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