Dibyajyoti Saha1* and Milan Hait2
1School of Pharmacy, Chouksey Engineering College, Lal Khadan, Masturi Road, Bilaspur-495004, (C.G). 2Dept. of Chemistry, Dr. C. V. Raman University, Kargi Road, Kota, Bilaspur, C.G.- 495113.
*Corresponding Author E-mail: firstname.lastname@example.org
DMBA is a polycyclic aromatic hydrocarbon which may be used as cancer initiator and croton oil is used as cancer promoter in murine skin which composed of phorbol esters. Formation of stable DMBA-DNA adduct can lead to the induction of mutation that activate proto-oncogen or inactivate tumor suppressor genes as an important event during tumor initiation. In mouse skin the promotion process like increased cell proliferation, suppression of apoatosis and induction of the production of ROS and RNS that cause increase membrane lipid peroxidation and decrease cellular antioxidant stores. ROS plays an important role in the process of mutagenesis and carcinogenesis specially tumor promotion. The main aim and rationally of this ontological design is very potent for screening of new cancer chemopreventive agents as well as anticancer drug development.
KEYWORDS: Carcinogenesis, Polycyclic aromatic hydrocarbon, DMBA, Croton oil.
Polycyclic aromatic hydrocarbons are ubiquitous environmental pollutants with high carcinogenic potencies that have linked to their etiology of skin cancer1. The skin following contact with substances such as petroleum product (e.g., tars and pitch etc.) The potent PAH is 7,12-Dimethylbenzene (a) anthracene (DMBA), which must be induced skin cancer in adult mice and for this activity it is very useful for screening of new cancer chemopreventive agents2.
7,12-DIMETHYLBENZENE (a) ANTHRACENE (DMBA): DMBA is a polycyclic aromatic hydrocarbon, considered to be one of the etiological factors for the mice cancers as well as human cancers through its presence in the environmental mixture and it also requires metabolic activation to deploy its carcinogenicity3. The metabolic pathway of DMBA has been shown in below:-
Croton oil is a well-known strong tumor promoter in murine skin4. It is mainly composed of phorbol esters. Its tumor-promoting potential has been related to the presence of TPA, a phorbol ester present in it as a major constituent. TPA has been shown to act as a strong tumor promoter. Treatment with TPA has been reported to induce a variety of changes in murine skin, including dark basal keratinocytes and sustained epidermal hyperplasia, reactive oxygen species formation in epidermis, elevated epidermal cycloxygenase5.
DMBA- CROTON OIL TWO STAGE MOUSE SKIN CARCINOGENESIS:
Murine skin carcinogenesis is a stepwise process, consisting of Inhibition, promotion, and progression6. DMBA is metabolised by CYP1A1 CYP1B1, the enzyme of CYP450 to the ultimate carcinogen 1,2-epoxide-3,4-diol DMBA which form adduct with DNA. This adducts leads to mutation, which are prerequisite for the development of tumor7.g
Fig.I : Metabolic Pathway of DMBA
Repeated topical application of tumor promoter croton oil on mouse skin involves both oxidative burst as well as inflammation by stimulating the generation of NO, reactive nitric oxide species (RNS) and reactive oxygen species (ROS) from Langerhans cells, macrophase, and non-phagocytic cells. ROS plays an important role in the process of mutagenesis and carcinogenesis particularly tumor promotion. They can induce lipid peroxidation, DNA strand break by modulating different biochemical pathways gene expression8.
MOLECULAR CHANGES DURING TWO STAGE SKIN CANCER INDUCED BY DMBA AND PROMOTED BY CROTON OIL:
Formation of stable DMBA-DNA adduct can lead to the induction of that activate proto-oncogene or inactivate tumor suppressor genes as an important event during tumor initiation. Mutation of c-Harvey (Ha)-ras oncogene may be involved in tumor initiation in mouse skin upon exposure to DMBA. Beside c-Ha-ras gene, two other Kirsten(Ki) and nuroblastoma(N) are present on different Chromosome9.
TUMOR PROMOTION IN MOUSE SKIN:
In mouse skin the promotion process like increased cell proliferation, suppression of the apoatosis and induction of the production of ROS and RNS that cause increase membrane lipid per-oxidation and decreased cellular antioxidant stores. The signal transduction pathway of tumor promotion involves a complex cascade of event that is initiated by the interaction TPA with protein Kinase C(PKc). This activities cyclooxygenase-2 (COX-2) which increases of Prostaglandin (PGE2) from arachidonic acid. The formation of PGE2 initiate cascade event for tumor promotion10.
1) Induction of Ornithine decarboxylase (ODC) activity
2) Induction of ODC initiate a series of events resulting in increase DNA and polyamines (Spermine, Spermidine and Putrescine) synthesis that have shown to play an important cell prolification.
3) Increase the expression of c-jun and c-fos and subsequent activation of activator protein (AP-1) which are also necessary for tumor promotion event.
PROPOSED MECHANISM OF SKIN TUMOR PROMOTION IN MOUSE BY CROTON OIL:
Fig.2 : Mechanism of skin tumor promotion in mouse by croton oil
Murine skin carcinogenesis is a stepwise process, consisting of initiation, promotion and progression is a classical design for the study of the genetic and biological changes involved in tumor promotion. This design is also used for screening of new cancer protective agent, as it display a preneoplastic condition during carcinogenesis in the form of papillomas, which are visible and can be confirmed histopathologically.
The authors are thankful to Dr. Jayanta Kr. Das (Ex. Research Associate), Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute, Kolkata for providing the valuable information regarding this matter.
1. UK Department of Health PRODIGY. Skin cancer an overview. Available from: URL: http://www.prodigy.nhs.uk/accessed 18th August/2005.
2. IpC, Vadhanavikit S, Ganthur H. (1995) Cancer chemoprevention by aliphatic selenocyanates: effect of chain length on inhibition of mammary tumors and DMBA adducts. Carcinogenesis 16, 35-38.
3. Das RK, Bhattacharya S. (2004) Inhibition of DMBA-Croton oil Two stage Mouse skin Carcinogenesis by Diphenylmethyl Selenocyanate through Modultion of Cutaneous Oxidative Stress and Inhibition of Nitric Oxide Production. Asian Pacific J. Cancer Prevention 5, 151-158.
4. Yaar M. Molecular Mechanism of Skin Aging. Advances In Dermatology. 10; 1995: 63-75.
5. Budunova IV. et al. Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis. Oncogene. 22; 2003: 3279-3287.
6. Di Giovanni J. Multistage Carcinogenesis in mouse skin. Pharmac Ther 47; 1992: 63-128.
7. Berenbulum I. The cocarcinogenic action of croton resin. Cancer Res 1; 1941: 44-48.
8. Saha D et al. Nanoselenium: Potential Boon and Novel Approaches for Cancer Chemoprevention. Research Journal of Pharmacology and Pharmacodynamics. 3(1); 2011: 15-16.
9. Bizub D et al. Mutagenesis of the Ha-ras oncogene in mouse skin tumors induced by PAH. Proc. Natl. Acad. Sci. USA. 83; 1986: 6048-6052.
10. Saha D et al. Organoselenium as a Cancer Chemopreventive agent against Carcinogenesis. Research Journal of Pharmacy and Technology. 4(3); 2011: 367-368.
Received on 05.09.2011 Accepted on 26.09.2011
© Asian Pharma Press All Right Reserved