Organoselenium as a Cancer Chemopreventive Agent against Carcinogenesis.

 

D. Saha1*, D. Mridha2, S. Mondal2, M. Jana2 and S. Kayal3

1School of Pharmacy, Chouksey Engineering College, Bilaspur- 495004, C.G. 2Dept. of Pharmacy, Bharat Technology, Banitabla, Uluberia-711316, W.B. 3Dept. of Pharmacy, Kanak Manjari Institute of Pharmaceutical Sciences, Rourkela-769015, Orissa.

*Corresponding Author E-mail: saha.dibyajyoti@gmail.com

 

ABSTRACT:

The mechanisms by which organoselenium compounds inhibit tumor formation during the initiation phase of carcinogenesis have been explored in vitro and in well defined animal model. Various organoselenium compounds were found to have the ability to decrease lipids and phospholipids hydroperoxide levels, hydrogen peroxide, thereby destroying the propagation of free radicals; reactive oxygen and nitric oxide species mediating cellular damage. Organoselenium may inhibit oxidative stress to cells that produce toxicity and malignant transformation of cells leading to cancer. Organoselenium compounds have received wide attention as possible cancer chemopreventive agent.

 

KEYWORDS: Organoselenium, Cancer chemoprevention, Carcinogenesis.

 


 

INTRODUCTION:

Cancer is the uncontrolled cellular growth, which is characterized by the unique property of metastasis. The genetic analysis of cancer is advancing rapidly as a result of recent development of techniques which allow study of the sequence of the DNA and the cloning, manipulation of genes1. The various carcinogenic agents are polycyclic hydrocarbons, aromatic amines and halides, diet, hormones, metals, polymer surfaces, ionizing ( x ray and γ ray, particle radiation), ultraviolet radiations (UVA and UVB), viruses (papova, herpes, retro and hepadna viruses), transgenesis by enhancer-promoter-oncogene construct selective breeding etc2,3. Polypeptide and steroid hormones, inert substances (plastic film carcinogenesis), alcoholic beverages (ethanol), specific dietary alterations (methyl deficiency, galactosamine excess), chemical with no DNA-reactive intermediates, calorie intake, etc also are carcinogenic agents or processes exhibiting no capacity for inducing direct structural DNA changes. Organoselenium may inhibit carcinogenesis by altering the manner in which the carcinogen is handled by the organism prior to time it reacts to critical target sites and secondly the agent acts later by altering the biologic properties of cells that already have been subjected to the effects of chemical carcinogens in the multistage process of carcinogenesis4,5. So, organoselenium compounds are one of the good agreements as a cancer chemopreventive agent against carcinogenesis.

 

CANCER CHEMOPREVENTION, CARCINOGENESIS AND ORGANOSELENIUM:

Cancer chemoprevention termed as control of cancer in which the occurrence of the disease is prevented by the administration of one or more chemical or biological substances6. Cancer incidence decreasing and mortality is the ultimate aim of chemoprevention. Chemopreventive agents are mainly classified into two groups. The first groups of compounds are effective against complete carcinogens. The second group includes compound effective against tumor promoters. Some compounds fall into both categories7. Angiogenesis inhibition blocks carcinogenesis by preventive progression to the invasive phenotype8.

 

Carcinogenesis defined as to describe the development of this in an active phenomenon induced by any one or several of a variety of agents i.e. physical, chemical, genetic biological, etc. Carcinogenesis by many small molecular weight chemical involves either a direct action of the chemical on cellular DNA or metabolism of the parent chemical to an active or ultimate foam, which can react with cellular DNA to produce a permanent chemical change in a DNA structure some characteristic features of the stages of carcinogenesis:- a) Initiation: Irreversible, Requires fixation, Additive, No threshold.

 

b) Promotion: Reversible, Environmentally modulated, Maximal response, Threshold.

c) Progression: Irreversible, Somatic aneuploidy, Progressive karyotypic instability.

Organoselenium compounds are chemical compounds containing carbon to selenium chemical bonds. The first organoselenium compound ever isolated was diethylselenide in 18369. The recent development non pharmacopoeia organoselenium drug is Diphenylmethyl selenocyanate and this drug showed cancer-chemopreventive activity against various type of cancer with its oxidative stress inhibition mechanism which prevent oxidative damage to cell that produce toxicity and also malignant transformation of cells. Organoselenium plays an important role as a component of glutathione per oxides an enzyme responsible preventing damage due to oxidative stress. In animal study, it is observed that its toxic if taken in excess dose. Various organoselenium compound were found to have the ability to decrease lipid and phospholipids hydroperoxide levels, hydrogen peroxide, thereby destroying the propagation of free radicals, reactive oxygen and nitric oxide species mediating cellular damage. These compounds or agents may help to prevent cancer by acting as an antioxidant or by enhancing immune activity10.

 

CHEMOPREVENTIVE EFFECT OF ORGANOSELENIUM ON DIFFERENT PHASES OF CARCINOGENESIS:

Superoxide anion radicals, hydrogen peroxide, hydroxyl radicals, peroxy radicals, nitric oxide radicals, etc are free radicals and molecules which cause oxidative stress. When free radicals are increased then oxidative damage and DNA damage are formed and thereafter produce cancer11.

In effect of initiation process, free radicals cause DNA damage presumably leading to mutation of affected cells, in preventing the initiation of carcinogenesis the antioxidant protection may be important. Organoselenium dependent GPxs and TR may play role in inhibiting initiation12.

Organoselenium has been found to be antitumorigenic when treated after the initiation phase in several models and it is termed as post initiation effect. Organoselenium is most effective when treatment is continuous, starting from initiation.

 

The basic approach of the metabolic activation of all procarcinogens is that the ultimate DNA-reactive carcinogenic species is electrophilic and these metabolites may themselves be reactive oxygen species, reactive nitrogen species, hydroxyl radicals, malonyldialdehyde that directly or indirectly are involved in multistage carcinogenesis. They can involve in DNA damage and acts as initiation and/or promoter in carcinogenesis. Organoselenium compounds that can modulate bodys antioxidant enzyme system (phase II enzymes) which can repair DNA and ultimately prevent cancer13,14.

 

CONCLUSION:

Organoselenium compounds are able to reduce hydrogen peroxide, lipids and phospholipids and also inhibiting the generation of ROS leading to DNA damage. Cancer chemopreventive activity of organoselenium may be due to the combined effect of enhancing detoxification enzyme activity and down regulation of LPO by controlling oxidative stress, which maintains the intracellular oxidation or reduction balance15. These compounds occur inhibition of carcinogen metabolism or formation or activation.

 

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Received on 26.10.2010 Modified on 13.11.2010

Accepted on 18.11.2010 RJPT All right reserved

Research J. Pharm. and Tech. 4(3): March 2011; Page 367-368