Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.736
5-Year Impact Factor – 2.135
Index Copernicus  – 168.52
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2020, vol. 29, nr 11, November, p. 1249–1254

doi: 10.17219/acem/127682

Publication type: original article

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Protective and therapeutic effects of pyrrolidine dithiocarbamate in a rat tongue cancer model created experimentally using 4-nitroquinoline 1-oxide

Aysenur Meric Hafız1,A, Remzi Doğan2,A,B,D, Zuhal Gucin3,B,C, Omer Faruk Ozer4,B,C, Alper Yenigun2,E, Orhan Ozturan2,F

1 Department of Otorhinolaryngology, Koc University, Istanbul, Turkey

2 Department of Otorhinolaryngology, Bezmialem Vakif University, Istanbul, Turkey

3 Department of Pathology, Bezmialem Vakif University, Istanbul, Turkey

4 Department of Biochemistry, Bezmialem Vakif University, Istanbul, Turkey


Background. Tongue tumors, which are oropharyngeal tumors, are increasing in frequency. Pyrrolidine dithiocarbamate (PDTC) is a powerful antioxidant and antitumoral agent.
Objectives. To evaluate the protective and therapeutic effects of PDTC in a tongue cancer model induced with 4-nitroquinoline 1-oxide (4-NQO).
Material and Methods. We included 40 rats in the trial and assigned them randomly to 5 groups. Group 1 (cancer, n = 7): 4-NQO (0–12 weeks); group 2 (protection, n = 8): 4-NQO (0–12 weeks) + PDTC (300 mg/kg/day, 0–12 weeks); group 3 (therapy-high dose, n = 10): 4-NQO (0–12 weeks) + PDTC (600 mg/kg/day, weeks 12–30); group 4 (therapy-low dose, n = 10): 4-NQO (0–12 weeks) + PDTC (300 mg/kg/day, weeks 12–30); and group 5 (control). Cardiac blood samples were taken to analyze oxidative stress parameters (total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI)). Histopathological assessment was performed under a light microscope.
Results. The results of the histopathological assessment showed that the model we used in group 1 was successful, which was consistent with the literature. The PDTC dose administered in group 2 could not prevent tumor formation. Group 3 demonstrated that PDTC in high doses is effective as a therapeutic agent. Group 4 indicated that PDTC in low doses has no therapeutic effect. The results of the biochemical assessment showed that in group 3, TOS and OSI values were significantly lower than in groups 1, 2 and 4. No significant difference was found in the TOS and OSI values between groups 5 and 3.
Conclusion. Our study demonstrated histopathologically that in an experimentally generated tongue cancer model, application of 600 mg/kg/day of PDTC led to a significant reduction in the size of the tumor. This was supported by the biochemical parameters.

Key words

antioxidant, tongue cancer, antitumoral, pyrrolidine dithiocarbamate, 4-nitroquinoline 1-oxide

References (34)

  1. Balanchaert RH. Epidemiology of oral cancer. In: Ord RA, Balanchaert RH, eds. Oral Cancer. Chicago, IL: Quitessence Publishing; 2000:3–8.
  2. Partridge M, Emilion G, Pateromichelakis S, Phillips E, Langdon J. Cancerisation of the oral cavity: Comparison of the spectrum of molecular alterations in cases presenting with both dysplastic and malignant lesions. Oral Oncol. 1997;33:332–337.
  3. Shklar G. Development of experimental oral carcinogenesis and its impact on current oral cancer research. J Dent Res. 1999;78(12):1768–1772.
  4. Kelloff GJ, Crowell JA, Steele VE, et al. Progress in cancer chemoprevention. Ann N Y Acad Sci. 1999;889:1–13.
  5. Tanaka T. Chemoprevention of oral carcinogenesis. Eur J Cancer. 1995;31(1):3–15.
  6. Orrenius S. Nobel CSI, van den Dobbelsteen DJ, Burkitt MJ, Slater AF. Dithiocarbamates and the redox regulation of cell death. Biochem Soc Trans. 1996;24(4):1032–1038.
  7. Iseki A, Kambe F, Okumura K, et al. Pyrrolidine dithiocarbamate inhibits TNF-α- dependent activation of NF-κB by increasing intracellular copper level in human aortic smooth muscle cells. Biochem Biophys Res Commun. 2000;276(1):88–92.
  8. Ross SD, Kron IL, Gangemi JJ, et al. Attenuation of lung reperfusion injury after transplantation using an inhibitor of nuclear factor-κB. Am J Physiol Lung Cell Mol Physiol. 2000;279(3):L528–L536.
  9. Schreck R, Meier B, Männel DN, Dröge W, Baeuerle PA. Dithiocarbamates as potent inhibitors of nuclear factor κB activation in intact cells. J Exp Med. 1992;175(5):1181–1194.
  10. Muller DN, Dechend R, Mervaala EMA, et al. NF-κB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. Hypertension. 2000;35(1 Pt 2):193–201.
  11. Liu SF, Ye X, Malik AB. Inhibition of NF-κB activation by pyrrolidine dithiocarbamate prevents in vivo expression of proinflammatory genes. Circulation. 1999;100(12):1330–1337.
  12. Borrello S, Demple B. NF kappa B-independent transcriptional induction of the human manganous superoxide dismutase gene. Arch Biochem Biophys. 1997;348(2):289–294.
  13. Wild AC, Mulcahy RT. Pyrrolidine dithiocarbamate upregulates the expression of the genes encoding the catalytic and regulatory subunits of γ-glutamylcysteine synthetase and increases intracellular glutathione levels. Biochem J. 1999;338(Pt 3):659–665.
  14. Nathens AB, Bitar R, Davreux C, et al. Pyrrolidine dithiocarbamate attenuates endotoxin-induced acute lung injury. Am J Resp Cell Mol Biol. 1997;17(5):608–616.
  15. Spiller SE, Logsdon NJ, Deckard LA, Sontheimer H. Inhibition of ­nuclear factor kappa-B signaling reduces growth in medulloblastoma in vivo. BMC Cancer. 2011;11:136.
  16. Yang C, Zhang H, Huang W, Lin Q, Wei H. Effect of combined use of PDTC and paclitaxel on proliferation and invasion of human breast cancer cell line MCF-7 [in Chinese]. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2010;27:1105–1109.
  17. Ribeiro D, Kitakawa D, Domingues MA, Cabral LA, Marques ME, Salvadori DM. Survivin and nitric oxide inducible synthase production during 4NQO-induced rat tongue carcinogenesis: A possible relationship. Exp Mol Pathol. 2007;83(1):131–137.
  18. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005;38(12):1103–1111.
  19. Erel O. A novel automated method to measure total antioxidant response against potent free radical reactions. Clin Biochem. 2004;37(2):112–119.
  20. Vural M, Camuzcuoglu H, Toy H, Aksoy N. Amniotic fluid prolidase activity and oxidative status in neural tube defects. Fetal Diagn Ther. 2010;28(1):34–39.
  21. Kademani D. Oral cancer. Mayo Clin Proc. 2007;82(7):878–887.
  22. Bachar G, Hod R, Goldstein DP, et al. Outcome of oral tongue squamous cell carcinoma in patients with and without known risk factors. Oral Oncol. 2011;47(1):45–50.
  23. Nagpal JK, Patnaik S, Das BR. Prevalence of high-risk human papilloma virus types and its association with P53 codon 72 polymorphism in tobacco addicted oral squamous cell carcinoma OSCC patients of Eastern India. Int J Cancer. 2002;97(5):649–653.
  24. Lippman SM, Sudbø J, Hong WK. Oral cancer prevention and the evolution of molecular-targeted drug development. J Clin Oncol. 2005;23(2):346–356.
  25. Haddadin KJ, Soutar DS, Webster MHC, Robertson AG, Oliver RJ, MacDonald DG. Natural history and patterns of recurrence of tongue tumors. Br J Plast Surg. 2000;53(4):279–285.
  26. Makita H, Mutoh M, Maruyama T. A prostaglandin E2 receptor subtype EP1-selective antagonist, ONO-8711, suppresses 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis. Carcinogenesis. 2007;28(3):677–684.
  27. Ji GQ, Chen RQ, Zheng JX. Macrophage activation by polysaccharides from Atractylodes macrocephala Koidz through the nuclear factor-kB pathway. Pharm Biol. 2015;53(4):512–517.
  28. Gao P, Gao YJ, Liang HL. Effect of NF-κB inhibitor PDTC on VEGF and endostatin expression of mice with Lewis lung cancer. Asian Pac J Trop Med. 2015;8(3):220–224.
  29. Cheng AC, Huang TC, Lai CS, et al. Pyrrolidine dithiocarbamate inhibition of luteolin-induced apoptosis through upregulated phosphorylation of Akt and caspase-9 in human leukemia HL-60 cells. J Agric Food Chem. 2006;54(12):4215–4221.
  30. Panizzi L, Catalano S, Miarelli C, Cioni PL, Campeol E. In vitro antimicrobial activity of extracts and isolated constituents of Geum rivale. Phytother Res. 2000;14(7):561–573.
  31. Minicucci EM, Ribeiro DA, da Silva GN, Pardini MI, Montovani JC, Salvadori DM. The role of the TP53 gene during rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide. Exp Toxicol Pathol. 2011;63(5):483–489.
  32. Miranda SR, Noguti J, Carvalho JG, Oshima CT, Ribeiro DA. Oxidative DNA damage is a preliminary step during rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide. J Mol Histol. 2011;42(2):181–186.
  33. Battisti C, Formichi P, Tripodi SA, Vindigni C, Roviello F, Federico A. Vitamin E serum levels and gastric cancer: Results from a cohort of patients in Tuscany, Italy. Cancer Lett. 2000;151(1):15–18.
  34. Doğan R, Meriç Hafiz A, Tugrul S, Ozturan O, Keskin S, Kocyigit A. Can oxidative stress parameters be used as biomarkers for the discrimination of malignant head and neck tumors. J Craniofac Surg. 2016;27(3):e316–e320.