Skip to main content

Advertisement

SpringerLink
Log in

Chemopreventive Efficacy of Naringenin-Loaded Nanoparticles in 7,12-dimethylbenz(a)anthracene Induced Experimental Oral Carcinogenesis

  • Research
  • Published:
Pathology & Oncology Research

Abstract

Nanochemoprevention has been introduced recently as a novel approach for improving phytochemicals bioavailability and anti-tumor effect. The present study is designed to evaluate the chemopreventive efficacy of prepared naringenin-loaded nanoparticles (NARNPs) relative to efficacy of free naringenin (NAR) against 7,12-dimethyl benz(a)anthracene (DMBA)-induced oral carcinogenesis by evaluating the status of lipid peroxidation, antioxidants and immunoexpression patterns of proliferating cell nuclear antigen (PCNA) and p53 proteins. Transmission electron microscope (TEM) and dynamic light scattering (DLS) investigations have confirmed a narrow size distribution of the prepared nanoparticles (40–90 nm) with ~88 % encapsulation efficiency. Oral squamous cell carcinoma (OSCC) was developed in the buccal pouch of golden Syrian hamsters by painting with 0.5 % DMBA in liquid paraffin three times a week for 14 weeks. DMBA painted animals revealed the morphological changes, hyperplasia, dysplasia and well-differentiated squamous cell carcinoma. Moreover, the status of lipid peroxidation, antioxidants and immunoexpression of PCNA and p53 were significantly altered during DMBA-induced oral carcinogenesis. Oral administration of NARNPs (50 mg NAR/kg body weight/day) to DMBA-treated animals completely prevented the tumor formation as compared to the free NAR and significantly reduced the degree of histological lesions, in addition to restoration of the status of biochemical and molecular markers during oral carcinogenesis. In addition, NARNPs have more potent anti-lipid peroxidative, antiproliferative effect and antioxidant potentials compared to free NAR in DMBA-induced oral carcinogenesis. In conclusion, the present study suggests that NARNPs could be a potentially useful drug carrier system for targeted delivery of naringenin for cancer chemoprevention.

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

Similar content being viewed by others

References

  1. Warnakulasurya S (2010) Living with oral cancer: epidemiology with particular reference to prevalence and life-style changes the influence survival. Oral Oncol 46:407–410

    Article  Google Scholar 

  2. Nagini S (2009) Of human and hamsters: the hamster buccal pouch carcinogenesis model as a paradigm for oral carcinogenesis and chemoprevention. Anti Cancer Agents Med Chem 9:843–852

    Article  CAS  Google Scholar 

  3. Dipple A, Piggot M, Moschel RC, Constantino N (1983) Evidence that binding of 7,12-dimethylbenz(a)anthracene to DNA in mouse embryo cell cultures results in extensive substitution of both adenine and guanine residues. Can Res 43:4132–4135

    CAS  Google Scholar 

  4. Shklar G (1999) Development of experimental oral carcinogenesis and its impact on current oral cancer research. J Dent Res 78:1768–1772

    Article  PubMed  CAS  Google Scholar 

  5. Nagini S, Vidjaya Letchoumy P, Thangavelu A, Ramachandran CR (2009) Of humans and hamsters: a comparative evaluation of carcinogen activation, DNA damage, cell proliferation apoptosis, invasive and angiogenesis in oral cancer patients and hamster buccal pouch carcinomas. Oral Oncol 45:31–37

    Article  Google Scholar 

  6. Harish kumar G, Vidya priyadarsini R, Vinothini G et al (2010) The neem limonoids azadirachtin and nimbolide inhibit cell proliferation and induce apoptosis in an animal model of oral oncogenesis. Invest New Drugs 28:392–401

    Article  PubMed  CAS  Google Scholar 

  7. Amaro MI, Helder Vila-Real JR, Eduardo-Figueira M et al (2009) Anti-inflammatory activity of naringin and biosynthesised naringenin by naringinase immomobilized in microstructured materials in a model of DDS-induced colitis in mice. Food Res Int 42:1010–1017

    Article  Google Scholar 

  8. Choi JS, Park KY, Moon SH, Rhee SH et al (1994) Antimutagenic effect of plant flavonoids in the salmonella assay system. Arch Pharm Res 17:71–75

    Article  PubMed  CAS  Google Scholar 

  9. Lee CH, Jeong TS, Choi YK et al (2001) Antiatherogenic effect of citrus flavonoids, naringin and naringenin, associated with hepatic ACAT and aorticVCAM-1 and MCP-1 in high cholesterol-fed rabbits. Biophys Res Commun 284:681–688

    Article  CAS  Google Scholar 

  10. Ekambaram G, Rajendran P, Magesh V, Sakthisekaran D (2008) Naringenin reduces tumor size and weight loss in N-methyl-N-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats. Nutr Res 28:106–112

    Article  PubMed  CAS  Google Scholar 

  11. Yen FL, Wu TH, Lin LT et al (2008) Naringenin-loaded nanoparticles improve the physicochemical properties and the hepatoprotective effect of naringenin in orally-administrated rats with CCl4-induced acute liver failure. Pharm Res 26:893–902

    Article  PubMed  Google Scholar 

  12. Wen J, Liu B, Yuan E, Ma Y et al (2010) Preperation and physicochemical properties of the complex of naringenin with hydroxypropyl-β-cyclodextrin. Molecules 15:4401–4447

    Article  PubMed  CAS  Google Scholar 

  13. Semalty A, Semalty M, Singh D, Rawat MSM (2010) Preparation and characterization of phospholipid complexes of naringenin for effective drug delivery. J Incl Phenom Macrocycl Chem 67:253–260

    Article  CAS  Google Scholar 

  14. Krishnakumar N, Sulfikkarali N, Rajendra Prasad N, Karthikeyan S (2011) Enhanced anticancer activity of naringenin-loaded nanoparticles in human cervical (HeLa) cancer cells. Biomed Prev Nutr 1:223–231

    Article  Google Scholar 

  15. Alonso JM (2004) Nanomedicines for overcoming biological barriers. Biomed Pharmacother 58:168–172

    Article  PubMed  Google Scholar 

  16. Siddiqui IA, Adhami VM, Bharali DJ et al (2009) Introducing nanochemoprevention as a novel approach for cancer control: proof of principle with green tea polyphenol epigallocatechin-3-gallate. Cancer Res 69:712–716

    Article  Google Scholar 

  17. Okhawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  Google Scholar 

  18. Beutler E, Kelly BM (1963) The effect of sodium nitrite on red cell GSH. Experientia 19:96–97

    Article  PubMed  CAS  Google Scholar 

  19. Rotruck JT, Pope AL, Ganther HE et al (1973) Selenium: biochemical role as component of gluthaione peroxidase. Science 179:588–599

    Article  PubMed  CAS  Google Scholar 

  20. Kakkar P, Das B, Viswanathan PN (1984) A modified spectrophotometric assay of superoxide dismutase. Indian J Biochem Biophys 21:130–132

    PubMed  CAS  Google Scholar 

  21. Sinha AK (1972) Calorimetric assay of catalase. Anal Biochem 47:389–394

    Article  PubMed  CAS  Google Scholar 

  22. Palan PR, Mikhail MS, Basu J, Romney SL (1991) Plasma levels of antioxidant beta-carotene and alpha-tocopherol in uterine cervix dysplasias and cancer. Nutr Cancer 15:13–20

    Article  PubMed  CAS  Google Scholar 

  23. Panjamurthy K, Manoharan S, Nirmal MR, Vellaichamy L (2009) Protective role of Withaferin-A on immuno expression of p53 and bcl-2 in 7, 12-dimethylbenz(a)anthracene-induced experimental oral carcinogenesis. Invest New Drugs 27:447–452

    Article  PubMed  CAS  Google Scholar 

  24. Lyzogubov V, Khozhaenko Y, Usenko V et al (2008) Immunohistochemical analysis of Ki-67, PCNA and S6K1/2 expression in human breast cancer. Exp Oncol 27:141–144

    Google Scholar 

  25. Acharya SDF, Sahoo SK (2009) Targeted epidermal growth factor receptor nanoparticle bioconjugates for breast cancer therapy. Biomaterials 30:5737–5750

    Article  PubMed  CAS  Google Scholar 

  26. Manoharan S, Vasanthaselvan M, Silvan S et al (2010) Carnosic acid: A potent chemopreventive agent against oral carcinogenesis. Chem Bio Inter 188:616–622

    Article  CAS  Google Scholar 

  27. Krishnakumar N, Manoharan S, Palaniappan PLRM (2009) Chemopreventive efficacy of piperine in 7,12-dimethylbenz(a)anthrazene(DMBA)-induced hamster buccal pouch carcinogenesis: an FT-IR study. Food Chem Toxicol 47:2813–2820

    Article  PubMed  CAS  Google Scholar 

  28. Wu G, Fang YZ, Yang S et al (2004) Glutathione metabolism and its implication for health. J Nutr 134:489–492

    PubMed  CAS  Google Scholar 

  29. Silvan S, Manoharan S, Baskaran N et al (2011) Chemopreventive potential of apigenin in 7, 12-dimethylbenz (a)anthracene induced experimental oral carcinogenices. Eur J Pharmcol 670:571–577

    Article  CAS  Google Scholar 

  30. McCormik D, Hall PA (1992) The complexities of proliferating cell nuclear antigen. Histopathology 21:591–594

    Article  Google Scholar 

  31. Shin DM, Voravud N, Ro JY et al (1993) Sequential increases in proliferating cell nuclear antigen expression in head and neck tumorigenesis: a potential biomarker. J Natl Cancer Int 85:971–978

    Article  CAS  Google Scholar 

  32. Chans KW, Sarraj S, Lin SS et al (2000) P53 expression, p53 and Ha-ras mutation and telomerase activation during nitrosamine-mediated hamster pouch carcinogenesis. Carcinogenesis 21:1441–1451

    Article  Google Scholar 

  33. Das N, Sahoo SK (2011) Epithelial cell adhesion molecule targeted nutlin-3a loaded immunonanoparticles for cancer therapy. Acta Biomaterialia 7:355–369

    Article  PubMed  CAS  Google Scholar 

  34. Mohanty C, Sahoo SK (2010) The in vitro stability and in vivo pharmacokinetics of curcumin prepared as an aqueous nanoparticulate formulation. Biomaterials 3:6597–6611

    Article  Google Scholar 

  35. Acharya S, Sahoo SK (2011) PLGA nanoparticles containing various anticancer agents and tumor delivery by EPR effect. Adv Drug Del 63:170–183

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors are thankful to the authorities of Annamalai University, for providing all necessary facilities to carry out the present study successfully. They also thank the anonymous referees, who significantly contributed to improving the contents of the manuscript.

Conflict of Interest Statement

The authors declare that they have no conflict of interest concerning this article.

Author information

Authors and Affiliations

  1. Department of Physics, Annamalai University, Annamalainagar, 608 002, Tamilnadu, India

    Nechikkad Sulfikkarali & Narendran Krishnakumar

  2. Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, 608 002, Tamilnadu, India

    Shanmugam Manoharan

  3. Department of Oral and Maxillofacial Pathology, Rajah Muthiah Dental College & Hospital, Annamalai University, Annamalainagar, 608 002, Tamilnadu, India

    Ramadas Madhavan Nirmal

Authors
  1. Nechikkad Sulfikkarali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Narendran Krishnakumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shanmugam Manoharan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ramadas Madhavan Nirmal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Narendran Krishnakumar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sulfikkarali, N., Krishnakumar, N., Manoharan, S. et al. Chemopreventive Efficacy of Naringenin-Loaded Nanoparticles in 7,12-dimethylbenz(a)anthracene Induced Experimental Oral Carcinogenesis. Pathol. Oncol. Res. 19, 287–296 (2013). https://doi.org/10.1007/s12253-012-9581-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-012-9581-1

Keywords

Search

Navigation