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Chemopreventive herbal anti-oxidants: current status and future perspectives.

Patel R, Garg R, Erande S, B Maru G - J Clin Biochem Nutr (2007)

Bottom Line: Anti-promotion strategies involve attenuation of enhanced cellular proliferation along with induction of cellular apoptosis and differentiation.Dietary agents or herbal anti-oxidants due to low toxicity and relative safety are promising chemopreventive agents.Complex issues such as choice and nutritional status of target population, genetic variation, gene-environment interactions and relevance of biomarkers analyzed also warrant further research and analyses.

View Article: PubMed Central - PubMed

Affiliation: Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi-Mumbai-410 208, India.

ABSTRACT
Cancer chemoprevention is fast becoming a lucrative approach for controlling cancer. Carcinogenesis being a complex multi-step, multi-factorial process, a number of chemopreventive interventions can be employed. These strategies are generally directed against two broad events of carcinogenesis viz., initiation and promotion/progression. Anti-initiation interventions principally involve inhibition of carcinogen activation, scavenging of free radicals and reactive carcinogen metabolites along with enhanced detoxification of carcinogens by modulating cellular metabolism. Anti-promotion strategies involve attenuation of enhanced cellular proliferation along with induction of cellular apoptosis and differentiation. Dietary agents or herbal anti-oxidants due to low toxicity and relative safety are promising chemopreventive agents. These agents after emerging successful through a series of in vitro and in vivo assays enter clinical trials. Many dietary compounds have emerged as promising chemopreventive agents in empirical experiments. However, in clinical trials these compounds have met with limited success. This emphasizes the need for further detailed research on the mechanisms of observed chemoprevention and choice, dose, duration and bioavailability of chemopreventive agent used. Complex issues such as choice and nutritional status of target population, genetic variation, gene-environment interactions and relevance of biomarkers analyzed also warrant further research and analyses.

No MeSH data available.


Related in: MedlinePlus

Schematic presentations of steps where chemopreventive agents can inhibit phase I enzyme induction. Chemopreventive agents can block the process of initiation by inhibiting xenobiotic induced transcriptional upregulation of phase I enzymes either by competing for receptor, inhibiting nuclear translocation of ligand and receptor complex or by inhibiting the binding of receptor ligand complex to specific promoter element. X = XAP2; 90 = heat shock protein 90; L = ligand (exogenous/endogenous); XRE = xenobiotic response element; C = chemopreventive agent.
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Figure 2: Schematic presentations of steps where chemopreventive agents can inhibit phase I enzyme induction. Chemopreventive agents can block the process of initiation by inhibiting xenobiotic induced transcriptional upregulation of phase I enzymes either by competing for receptor, inhibiting nuclear translocation of ligand and receptor complex or by inhibiting the binding of receptor ligand complex to specific promoter element. X = XAP2; 90 = heat shock protein 90; L = ligand (exogenous/endogenous); XRE = xenobiotic response element; C = chemopreventive agent.

Mentions: Cellular metabolism plays a very critical role in the process of initiation during carcinogenesis [4]. Xenobiotics entering the cellular environment are metabolized by phase I and phase II enzymes. Phase I enzymes, predominantly Cytochrome P450s (CYP450s—a super family of heme-thiolate enzymes), are involved in the first step of metabolism where xenobiotics are processed to more electrophilic moieties for further detoxification by phase II enzymes [5]. This step can be termed as bioactivation which renders pro-carcinogens to reactive intermediates and these in turn can form bio-molecular adducts e.g. DNA-adducts, protein-adducts etc. which mark the process of initiation. Thus, decreased activation of carcinogens due to modulation of the CYP 450 enzymes could be one of the plausible targets for chemoprevention to prevent the cancer initiation process. CYP1-CYP9 family of enzymes which are principally involved in xenobiotic metabolism have distinct substrate specificities and are differentially regulated by different ligands which interact with endogenous receptors like aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR). AhR is one of the well studied receptors involved in induction of CYP1A sub-family enzymes which are primarily involved in metabolizing xenobiotics like poly aromatic hydrocarbons (PAHs). AhR is a ligand dependent transcription factor and member of the basic-helix-loop-helix family. In an unliganded or inactive state the receptor is present in the cytoplasm in a complex with two molecules of molecular chaperones, hsp90, an immunophilin like protein, XAP-2 and the hsp90 interacting protein, p23. Upon ligand binding, the ligand-AhR-hsp90-XAP2-p23 complex translocates to nucleus where hsp90-XAP2-p23 dissociates from the ligand-AhR complex. This ligand-AhR complex further associates with a structurally related protein, AhR nuclear translocator (ARNT). This ligand bound AhR-ARNT complex recognizes consensus sequences termed xenobiotic response elements (XREs) to modulate the expression of downstream genes. Certain chemopreventive agents, like plant flavanoids, have shown to act as natural ligands of AhR and hence not only compete for binding with PAHs but also block subsequent nuclear translocation and DNA binding followed by transactivation of CYP genes [6]. Such agents, that can block pro-carcinogen activation, can serve as potential blockers of initiation of carcinogenesis (Fig. 2).


Chemopreventive herbal anti-oxidants: current status and future perspectives.

Patel R, Garg R, Erande S, B Maru G - J Clin Biochem Nutr (2007)

Schematic presentations of steps where chemopreventive agents can inhibit phase I enzyme induction. Chemopreventive agents can block the process of initiation by inhibiting xenobiotic induced transcriptional upregulation of phase I enzymes either by competing for receptor, inhibiting nuclear translocation of ligand and receptor complex or by inhibiting the binding of receptor ligand complex to specific promoter element. X = XAP2; 90 = heat shock protein 90; L = ligand (exogenous/endogenous); XRE = xenobiotic response element; C = chemopreventive agent.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2127226&req=5

Figure 2: Schematic presentations of steps where chemopreventive agents can inhibit phase I enzyme induction. Chemopreventive agents can block the process of initiation by inhibiting xenobiotic induced transcriptional upregulation of phase I enzymes either by competing for receptor, inhibiting nuclear translocation of ligand and receptor complex or by inhibiting the binding of receptor ligand complex to specific promoter element. X = XAP2; 90 = heat shock protein 90; L = ligand (exogenous/endogenous); XRE = xenobiotic response element; C = chemopreventive agent.
Mentions: Cellular metabolism plays a very critical role in the process of initiation during carcinogenesis [4]. Xenobiotics entering the cellular environment are metabolized by phase I and phase II enzymes. Phase I enzymes, predominantly Cytochrome P450s (CYP450s—a super family of heme-thiolate enzymes), are involved in the first step of metabolism where xenobiotics are processed to more electrophilic moieties for further detoxification by phase II enzymes [5]. This step can be termed as bioactivation which renders pro-carcinogens to reactive intermediates and these in turn can form bio-molecular adducts e.g. DNA-adducts, protein-adducts etc. which mark the process of initiation. Thus, decreased activation of carcinogens due to modulation of the CYP 450 enzymes could be one of the plausible targets for chemoprevention to prevent the cancer initiation process. CYP1-CYP9 family of enzymes which are principally involved in xenobiotic metabolism have distinct substrate specificities and are differentially regulated by different ligands which interact with endogenous receptors like aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR). AhR is one of the well studied receptors involved in induction of CYP1A sub-family enzymes which are primarily involved in metabolizing xenobiotics like poly aromatic hydrocarbons (PAHs). AhR is a ligand dependent transcription factor and member of the basic-helix-loop-helix family. In an unliganded or inactive state the receptor is present in the cytoplasm in a complex with two molecules of molecular chaperones, hsp90, an immunophilin like protein, XAP-2 and the hsp90 interacting protein, p23. Upon ligand binding, the ligand-AhR-hsp90-XAP2-p23 complex translocates to nucleus where hsp90-XAP2-p23 dissociates from the ligand-AhR complex. This ligand-AhR complex further associates with a structurally related protein, AhR nuclear translocator (ARNT). This ligand bound AhR-ARNT complex recognizes consensus sequences termed xenobiotic response elements (XREs) to modulate the expression of downstream genes. Certain chemopreventive agents, like plant flavanoids, have shown to act as natural ligands of AhR and hence not only compete for binding with PAHs but also block subsequent nuclear translocation and DNA binding followed by transactivation of CYP genes [6]. Such agents, that can block pro-carcinogen activation, can serve as potential blockers of initiation of carcinogenesis (Fig. 2).

Bottom Line: Anti-promotion strategies involve attenuation of enhanced cellular proliferation along with induction of cellular apoptosis and differentiation.Dietary agents or herbal anti-oxidants due to low toxicity and relative safety are promising chemopreventive agents.Complex issues such as choice and nutritional status of target population, genetic variation, gene-environment interactions and relevance of biomarkers analyzed also warrant further research and analyses.

View Article: PubMed Central - PubMed

Affiliation: Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi-Mumbai-410 208, India.

ABSTRACT
Cancer chemoprevention is fast becoming a lucrative approach for controlling cancer. Carcinogenesis being a complex multi-step, multi-factorial process, a number of chemopreventive interventions can be employed. These strategies are generally directed against two broad events of carcinogenesis viz., initiation and promotion/progression. Anti-initiation interventions principally involve inhibition of carcinogen activation, scavenging of free radicals and reactive carcinogen metabolites along with enhanced detoxification of carcinogens by modulating cellular metabolism. Anti-promotion strategies involve attenuation of enhanced cellular proliferation along with induction of cellular apoptosis and differentiation. Dietary agents or herbal anti-oxidants due to low toxicity and relative safety are promising chemopreventive agents. These agents after emerging successful through a series of in vitro and in vivo assays enter clinical trials. Many dietary compounds have emerged as promising chemopreventive agents in empirical experiments. However, in clinical trials these compounds have met with limited success. This emphasizes the need for further detailed research on the mechanisms of observed chemoprevention and choice, dose, duration and bioavailability of chemopreventive agent used. Complex issues such as choice and nutritional status of target population, genetic variation, gene-environment interactions and relevance of biomarkers analyzed also warrant further research and analyses.

No MeSH data available.


Related in: MedlinePlus