Skip to main content

Advertisement

SpringerLink
Log in

3, 3′-Diindolylmethane-encapsulated chitosan nanoparticles accelerate molecular events during chemical carcinogen-induced mammary cancer in Sprague Dawley rats

  • Original Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

A Correction to this article was published on 30 September 2020

This article has been updated

Abstract

Background

3, 3′-Diindolylmethane (DIM) is a dietary indole compound; its medical application was limited because of poor bioavailability, unsatisfying dispersity, and rapid metabolism. To conquer this problem, nanoformulation of DIM was synthesized and investigated its mechanism-based chemotherapeutic potential.

Methods

7,12-Dimethylbenz(a)anthracene (DMBA) 25 mg/kg b.wt initiated mammary carcinogenesis in rats, the investigational tumor model that closely resembles human mammary cancer. Rats had accessed after 8 weeks of tumor formation, DIM 10 mg/kg b.wt. and DIM@CS-NP 0.5 mg/kg b.wt. were administrated orally for 8 weeks.

Results

The treatment with DIM@CS-NP 0.5 mg/kg b.wt. on DMBA-induced tumor-bearing rats was down-regulated Cyclin D1, Bcl-2 expression, and up-regulated proapoptotic proteins such as Bax, p53, Cytochrome-C, Caspase-9, and Caspase-3 as compared to DIM 10 mg/kg b.wt. In addition, the mRNA expressions of Cyclin D1, Bcl-2 decreased and increased Bax, p53 expression, in immunohistochemical analysis decreased expressions of Cyclin D1 and PCNA in the treatment of DIM@CS-NP 0.5 mg/kg b.wt. compared to DIM 10 mg/kg b.wt. Histological analysis of tumor tissues shows abnormal in collagen deposition in with Masson’s trichrome (MT) and Picrosirius red (PR) staining, the treatment of DIM@CS-NP 0.5 mg/kg b.wt. reduced the collagen deposition as compared to DIM 10 mg/kg b.wt.

Conclusion

Our results clearly provide evidence that DIM@CS-NP exerts chemotherapeutic effect than DIM in DMBA model of mammary cancer by hold back anomalous tumor cell proliferation and inducing apoptosis to intervene through alterations of up-regulated and down-regulated molecules. Taken together, the data provide new evidence for mechanism action of DIM@CS-NP on mammary cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Change history

  • 30 September 2020

    In the original publication of the article.

References

  1. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release. 2000;65:271–84.

    Article  CAS  Google Scholar 

  2. Blanco E, Ferrari M. Emerging nanotherapeutic strategies in breast cancer. Breast. 2014;23:10–8.

    Article  Google Scholar 

  3. Hu Y, Jiang X, Ding Y, Ge H, Yuan Y, Yang C. Synthesis and characterization of chitosan-poly(acrylic acid) nanoparticles. Biomaterials. 2002;15:3193–201.

    Article  Google Scholar 

  4. Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin. 1999;49:33–64.

    Article  CAS  Google Scholar 

  5. Michor F, Iwasa Y, Nowak MA. Dynamics of cancer progression. Nat Rev Cancer. 2004;4:197–205.

    Article  CAS  Google Scholar 

  6. De Vicente JC, Lequerica-Fernandez P, Santamaria J, Fresno MF. Expression of MMP-7 and MT1-MMP in oral squamous cell carcinoma as predictive indicator for tumor invasion and prognosis. J Oral Pathol Med. 2007;36:415–24.

    Article  Google Scholar 

  7. Muggia F, Safra T, Dubeau L. BRCA genes: lessons learned from experimental and clinical cancer. Ann Oncol. 2011;22(Suppl 1):i7–10.

    Article  Google Scholar 

  8. Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells over expressing prostaglandin endoperoxide synthase 2. Cell. 1995;83:493–501.

    Article  CAS  Google Scholar 

  9. Isabella S, Mirunalini S, Pandiyan K. 3,3′-Diindolylmethane encapsulated chitosan nanoparticles accelerates inflammatory markers, ER/PR, glycoprotein and mast cells population during chemical carcinogen induced mammary cancer in rats. Ind J Clin Biochem. 2018;33:397–405.

    Article  CAS  Google Scholar 

  10. Costantini P, Jacotot E, Decaudin D, Kroemer G. Mitochondrion as a novel target of anticancer chemotherapy. J Natl Cancer Inst. 2000;92:1042–53.

    Article  CAS  Google Scholar 

  11. Temple NT, Gladwin KK. Fruit, vegetables, and the prevention of cancer: research challenges. Nutrition. 2003;19:467–70.

    Article  Google Scholar 

  12. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46:3–26.

    Article  CAS  Google Scholar 

  13. Reed GA, Sunega JM, Sullivan DK, Gray JC, Mayo MS, Crowell JA, Hurwitz A. Single-dose pharmacokinetics and tolerability of absorption-enhanced 3,3′-diindolylmethane in healthy subjects. Cancer Epidemiol Biomark Prevent. 2008;17:2619–24.

    Article  CAS  Google Scholar 

  14. Anderton MJ, Manson MM, Verschoyle RD, Gescher A, Lamb JH. Pharmacokinetics and tissue disposition of indole-3-carbinol and its acid condensation products after oral administration to mice. Clin Cancer Res. 2004;10:5233–41.

    Article  CAS  Google Scholar 

  15. Fang M, Yuan J, Peng C, Li Y. Collagen as a double edged sword in tumor progression. Tumour Biol. 2014;35(4):2871–82. https://doi.org/10.1007/s13277-013-1511-7.

    Article  CAS  PubMed  Google Scholar 

  16. Welsch CW. Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: a review and tribute to Charles Brenton Huggins. Can Res. 1985;45:3415–43.

    CAS  Google Scholar 

  17. Isabella S, Mirunalini S. Chemotherapeutic effect of 3,3′-diindolylmethane encapsulated chitosan nanoparticles on 7,12-dimethylbenz(a) anthracene induced mammary cancer—a dose dependent study. New Horizons Transl Med. 2016;3:1–8.

    Google Scholar 

  18. Young B, Heath JW. Wheater’s functional histology: a text and color atlas. 2000.4th ed. Philadelphia: Churchill Livingstone.

  19. Lakshmi A, Sorimuthu Pillai S. Tangeretin a citrus pentamethoxyflavone, Exerts cytostatic effect via p53/p21 up-regulation and suppresses metastasis in 7,12-dimethylbenz(α)anthracene-induced rat mammary carcinoma. J Nutr Biochem. 2014;25:1140–53.

    Article  Google Scholar 

  20. Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970;227:680–85.

    Article  CAS  Google Scholar 

  21. Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987;162:156–9.

    Article  CAS  Google Scholar 

  22. Mohanty S, Jena P, Mehta R, Pati R, Banerjee B, Patil S, Sonawan A. Cationic antimicrobial peptides and biogenic silver nanoparticles kill mycobacteria without eliciting DNA damage and cytotoxicity in mouse macrophages. AAC ASM Org. 2013;57:3688–98.

    Article  CAS  Google Scholar 

  23. Luparello C. Aspects of Collagen Changes in breast cancer. J Carcinog Mutagen. 2013;S13:007. https://doi.org/10.4172/2157-2518.S13-007.

    Article  CAS  Google Scholar 

  24. Fang M, Yuan J, Peng C, Li Y. Collagen as a double-edged sword in tumor progression. Tumour Biol. 2014;35:2871–82.

    Article  CAS  Google Scholar 

  25. Paunesku T, Mittal S, Protic M, Oryhon J, Korolev SV. Proliferating cell nuclear antigen (PCNA): ringmaster of the genome. Int J Radiat Biol. 2001;77:1007–21.

    Article  CAS  Google Scholar 

  26. Wakui S, Yokoo K, Takahashi H, Mutoc T, Suzuki Y. CYP1 and AhR expression in 7,12-dimethylbenz[a]anthracene-induced mammary carcinoma of rats prenatally exposed to 3,3,4,4,5-pentachlorobiphenyl. Toxicology 2005;211:231–41.

    Article  CAS  Google Scholar 

  27. Mohammadizadeh F, Hani M, Ranaee M, Bagheri M. Role of cyclin D1 in breast carcinoma. J Res Med Sci. 2013;18:1021–25.

    PubMed  PubMed Central  Google Scholar 

  28. Wong RSY. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res CR. 2011;30:87.

    Article  CAS  Google Scholar 

  29. Shah S, Gapor A, Sylvester PW. Role of caspase-8 activation in mediating vitamin E-induced apoptosis in murine mammary cancer cells. J Nutr Cancer. 2003;45:2236–46.

    Google Scholar 

  30. James S. Lawson and Benjamin Heng viruses and breast cancer. Cancers. 2010;2:752–72.

    Article  Google Scholar 

  31. Sarkar FH, Rahman KM, Li Y. Bax translocation to mitochondria is an important event in inducing apoptotic cell death by indole-3-carbinol (I3C) treatment of breast cancer cells. J Nutr. 2003;133:2434–39.

    Article  Google Scholar 

  32. Lindsay J, Esposti MD, Gilmore AP. Bcl-2 proteins and mitochondria specificity in membrane targeting for death. Biochim Biophys Acta. 2011;1813:532–39.

    Article  CAS  Google Scholar 

  33. Hong C, Firestone GL, Bjeldanes LF. Bcl-2 family-mediated apoptotic effects of 3,3′-diindolylmethane (DIM) in human breast cancer cells. Biochem Pharmacol. 2002;63:1085–97.

    Article  CAS  Google Scholar 

  34. Kollmann K, Heller G, Schneckenleithner C, Warsch W, Scheicher R. A kinase-independent function of CDK6 links the cell cycle to tumor angiogenesis. Cancer Cell. 2013;24:167–81.

    Article  CAS  Google Scholar 

  35. Carter TH, Liu K, Ralph W, Chen D, Qi M. Diindolylmethane alters gene expression in human keratinocytes in vitro. J Nutr. 2002;132:3314–24.

    Article  CAS  Google Scholar 

  36. Abdel-Wahhab MA, Aljawish A, El-Nekeety AA, Abdel-Aziem SH, Hassan NS. Chitosan nanoparticles plus quercetin suppress the oxidative stress, modulate DNA fragmentation and gene expression in the kidney of rats fed ochratoxin A-contaminated diet. Food Chem Toxicol. 2017;99:209–21.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Dr. K. Pandiyan, Associate Professor, Department of Inorganic Chemistry, University of Madras, Guindy Campus, Chennai-600 025, Tamil Nadu, India for nanoparticles synthesis and characterization studies.

Funding

No funding source.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar, Chidambaram, Tamil Nadu, 608 002, India

    Stainsloss Isabella & Sankaran Mirunalini

Authors
  1. Stainsloss Isabella
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sankaran Mirunalini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sankaran Mirunalini.

Ethics declarations

Conflict of interest

The first author (S. Isabella) and the corresponding author (Dr. S. Mirunalini) declare that there are no conflicts of interest.

Ethical approval

This study was approved by the Institutional Animal Ethics Committee (IAEC), regulated by the Committee for the Purpose of Control and Supervision of Experimental Animals (CPCSEA) (Reg No. 160/1999/CPCSEA and Proposal No. 1123).

Informed consent

This article does not contain any studies with human participants.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Isabella, S., Mirunalini, S. 3, 3′-Diindolylmethane-encapsulated chitosan nanoparticles accelerate molecular events during chemical carcinogen-induced mammary cancer in Sprague Dawley rats. Breast Cancer 26, 499–509 (2019). https://doi.org/10.1007/s12282-019-00950-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-019-00950-x

Keywords

Search

Navigation