SINAPIC ACID ATTENUATES 7,12-DIMETHYLBENZ[A] ANTHRACENE-INDUCED ORAL CARCINOGENESIS BY IMPROVING THE APOPTOTIC ASSOCIATED GENE EXPRESSION IN HAMSTERS
Objectives: The main objective of the present study is to examine the histological changes and apoptotic associated gene expression during
7,12-dimethylbenz[a] anthracene (DMBA)-induced buccal pouch carcinogenesis in male golden Syrian hamsters.
Methods: Squamous cell carcinoma was induced in the buccal pouch of male Syrian golden hamsters by painting with 0.5% solution of DMBA in liquid
paraffin 3 times per week for 16 weeks to induce the development of oral tumors. Sinapic acid (50 mg/kg b.wt) were either applied topically to the
oral tumor lesions or administrated orally at varying dosage to hamster animals with oral tumor for 14 weeks. The experiment was terminated at the
end of 16
weeks. The development of oral carcinogenesis was confirmed by the histopathological analysis and expressions of apoptotic associated
genes were analyzed by the immunohistochemical methods.
Results: We observed altered status of apoptotic associated gene expression (P53, B-cell lymphoma [Bcl-2], Bax, and caspase-3) was observed
in the DMBA alone painted hamsters as compared to control hamsters. Oral administration of sinapic acid improved the histological changes and
significantly stimulate the apoptotic associated genes expression, especially caspase-3 but decreasing Bcl-2 protein production.
Conclusion: It can be evident from the findings of this research work concluded that oral administration of sinapic acid are effective at inhibiting
tumor cell proliferation and stimulating apoptosis in oral cancer suggesting that sinapic acid have chemopreventive effects on DMBA-induced
experimental oral carcinogenesis.
Keywords: Apoptosis, 7,12-dimethylbenz[a] anthracene, Hamster, Histology, Sinapic acid.
Woolgar JA, et al. Advances and applications of oral cancer basic
research. Oral Oncol 2011;47(9):783-91.
2. Williams HK. Molecular pathogenesis of oral squamous carcinoma.
Mol Pathol 2000;53(4):165-72.
3. Weinberg WC, Brown PD, Stetler-Stevenson WG, Yuspa SH.
Modulation of hair follicle cell proliferation and collagenolytic activity
by specific growth factors. Ann N Y Acad Sci 1991;642:281-90.
4. Cheng L, Wang X, Zhang J, Zhang SB, Zheng SQ, Zheng J. Targeting
apoptosis signaling pathways in cancer therapy. Zhonghua Bing Li Xue
Za Zhi 2009;38(9):639-42.
5. Green DR, Martin SJ. The killer and the executioner: How apoptosis
controls malignancy. Curr Opin Immunol 1995;7(5):694-703.
6. Rivlin N, Brosh R, Oren M, Rotter V. Mutations in the p53 tumor
suppressor gene: Important milestones at the various steps of
tumorigenesis. Genes Cancer 2011;2(4):466-74.
7. Soussi T. The p53 tumor suppressor gene: From molecular biology to
clinical investigation. Ann N Y Acad Sci 2000;910:121-37.
8. Gong XF, Wang MW, Tashiro S, Onodera S, Ikejima T. Pseudolaric acid
B induces apoptosis through p53 and Bax/Bcl-2 pathways in human
melanoma A375-S2 cells. Arch Pharm Res 2005;28(1):68-72.
9. Aman U, Vaibhav P, Balaraman R. Tomato lycopene attenuates
myocardial infarction induced by isoproterenol: Electrocardiographic,
biochemical and anti-apoptotic study. Asian Pac J Trop Biomed
10. da Silva SR, Bacchi MM, Bacchi CE, de Oliveira DE. Human bcl-2
expression, cleaved caspase-3, and KSHV LANA-1 in Kaposi sarcoma
lesions. Am J Clin Pathol 2007;128(5):794-802.
11. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo
with a conserved homolog, bax, that accelerates programmed cell
death. Cell 1993;74(4):609-19.
12. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development
and therapy. Oncogene 2007;26(9):1324-37.
13. Garg NK, Mangal S, Sahu T, Mehta A, Vyas SP, Tyagi RK. Evaluation
of anti-apoptotic activity of different dietary antioxidants in renal
cell carcinoma against hydrogen peroxide. Asian Pac J Trop Biomed
14. Gogvadze V, Orrenius S, Zhivotovsky B. Multiple pathways of
cytochrome c release from mitochondria in apoptosis. Biochim Biophys
15. Kumar SV, Saravanan D, Kumar B, Jayakumar A. An update on
prodrugs from natural products. Asian Pac J Trop Med 2014;7S1:S54-9.
16. Zou Y, Kim AR, Kim JE, Choi JS, Chung HY. Peroxynitrite scavenging
activity of sinapic acid (3,5-dimethoxy-4-hydroxycinnamic acid)
isolated from Brassica juncea. J Agric Food Chem 2002;50(21):5884-90.
17. Shin DS, Kim KW, Chung HY, Yoon S, Moon JO. Effect of sinapic acid
against carbon tetrachloride-induced acute hepatic injury in rats. Arch
Pharm Res 2013;36(5):626-33.
18. Zeng X, Zheng J, Fu C, Su H, Sun X, Zhang X, et al. A newly
synthesized sinapic acid derivative inhibits endothelial activation
in vitro and in vivo. Mol Pharmacol 2013;83(5):1099-108.
19. Kwak SY, Yang JK, Choi HR, Park KC, Kim YB, Lee YS. Synthesis
and dual biological effects of hydroxycinnamoyl phenylalanyl/prolyl
hydroxamic acid derivatives as tyrosinase inhibitor and antioxidant.
Bioorg Med Chem Lett 2013;23(4):1136-42.
20. Akhter S, Green JR, Root P, Thatcher GJ, Mutus B. Peroxynitrite and
NO donors form colored nitrite adducts with sinapinic acid: Potential
applications. Nitric Oxide 2003;8(4):214-21.
21. Mariadoss AV, Kathiresan S, Muthusamy R, Kathiresan S. Protective
effects of -paradol on histological lesions and immunohistochemical
gene expression in DMBA induced hamster buccal pouch
carcinogenesis. Asian Pac J Cancer Prev 2013;14(5):3123-9.
22. Geren RJ, Greenberg NH, Mcdonald MM, Schumacher AM.
Protocols for screening chemical agents and natural products against
animal tumors and other biological systems. Cancer Chemother Rep
23. Klitgaard H. A model for quantitative strength training of hindlimb
muscles of the rat. J Appl Physiol 1988;64(4):1740-5.
24. Cotran RS, Kumar V, Robbins SL. Pathologic basis of disease.
Philadelphia, Pennsylvania: 160(1); 1994.
25. Andrejevic S, Savari JF, Fontolliet C, Monnier PH, Bergh HV.
7,12- Dimethylbenz[a]anthracene-induced â€˜earlyâ€™ squamous-cell
carcinoma in the Golden Syrian hamster: Evaluation of an animal
model and comparison with â€˜earlyâ€™ forms of human squamouscell
carcinoma in the upper aero-digestive tract. Int J Exp Pathol
26. Anand MA, Suresh K. Biochemical profiling and chemopreventive
activity of phloretin on 7,12-Dimethylbenz (a) anthracene induced
oral carcinogenesis in male golden Syrian hamsters. Toxicol Int
27. Barnes DM, Hanby AM, Gillett CE, Mohammed S, Hodgson S,
Bobrow LG, et al. Abnormal expression of wild type p53 protein in
normal cells of a cancer family patient. Lancet 1992;340(8814):259-63.
28. Khan A, Shukla Y, Kalra N, Alam M, Ahmad MG, Hakim SR,
et al. Potential of diallyl sulfide bearing pH-sensitive liposomes in
chemoprevention against DMBA-induced skin papilloma. Mol Med
29. Kampa M, Alexaki VI, Notas G, Nifli AP, Nistikaki A, Hatzoglou A,
et al. Antiproliferative and apoptotic effects of selective phenolic acids
on T47D human breast cancer cells: Potential mechanisms of action.
Breast Cancer Res 2004;6(2):R63-74.
30. Rao CV, Patlolla JM, Qian L, Zhang Y, Brewer M, Mohammed A, et al.
Chemopreventive effects of the p53-modulating agents CP-31398 and
Prima-1 in tobacco carcinogen-induced lung tumorigenesis in A/J mice.
31. Lamson DW, Brignall MS. Natural agents in the prevention of cancer,
part two: Preclinical data and chemoprevention for common cancers.
Altern Med Rev 2001;6(2):167-87.
32. Hastak K, Gupta S, Ahmad N, Agarwal MK, Agarwal ML, Mukhtar H.
Role of p53 and NF-kappaB in epigallocatechin-3-gallate-induced
apoptosis of LNCaP cells. Oncogene 2003;22(33):4851-9.
33. Katiyar SK, Roy AM, Baliga MS. Silymarin induces apoptosis primarily
through a p53-dependent pathway involving Bcl-2/Bax, cytochrome c
release, and caspase activation. Mol Cancer Ther 2005;4(2):207-16.
34. Kirkin V, Joos S, ZÃ¶rnig M. The role of Bcl-2 family members in
tumorigenesis. Biochim Biophys Acta 2004;1644(2-3):229-49.
35. Puangpraphant S, Berhowb MA, De Mejia EG. Mate (Ilex paraguariensis
St. Hilaire) saponins induce caspase-3-dependent apoptosis in human
colon cancer cells in vitro. Food Chem 2010;125(4):1171-8.
36. Prasad S, Kalra N, Srivastava S, Shukla Y. Regulation of oxidative
stress-mediated apoptosis by diallyl sulfide in DMBA-exposed Swiss
mice. Hum Exp Toxicol 2008;27(1):55-63.
37. Hu X, Bardhan K, Paschall AV, Yang D, Waller JL, Park MA, et al.
Deregulation of apoptotic factors Bcl-xL and Bax confers apoptotic
resistance to myeloid-derived suppressor cells and contributes to their
persistence in cancer. J Biol Chem 2013;288(26):19103-15.
38. Rahmani M, Aust MM, Attkisson E, William DC, Ferreira-Gonzalez A,
Grant S. Inhibition of Bcl-2 anti-apoptotic members by obatoclax potently
enhances sorafenib-induced apoptosis in human myeloid leukemia cells
through a Bim-dependent process. Blood 2012;119(25):6089-98.
39. Rajasekaran D, Manoharan S. Silvan S, Vasudevan K, Baskaran N,
Palanimuthu D. Pro-apoptotic, anti-cell proliferative, antiinflammatory
Asian J Pharm Clin Res, Vol 8, Issue 6, 2015, 228-233
Kalaimathi and Suresh
40. Parrish AB, Freel CD, Kornbluth S. Cellular mechanisms controlling
caspase activation and function. Cold Spring Harb Perspect
41. Bascones-Martinez A, Rodriguez-Gutierrez C, Rodriguez-Gomez E,
Gil-Montoya JA, Gomez-Font R, Gonzalez-Moles MA. Evaluation
of p53, caspase-3, Bcl-2, and Ki-67 markers in oral squamous cell
carcinoma and premalignant epithelium in a sample from Alava
Province (Spain). Med Oral Patol Oral Cir Bucal 2013;18(6):e846-50.
42. Burton PB, Anderson CJ, Corbishly CM. Caspase 3 and
p27 as predictors of invasive bladder cancer. N Engl J Med
43. Munshi A, Pappas G, Honda T, McDonnell TJ, Younes A, Li Y, et al.
TRAIL (APO- 2L) induces apoptosis in human prostate cancer cells
that is inhabitable by Bcl-2. Oncogene 2001;20(29):3757-65.
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