Trends in Pharmacological Sciences
Dietary cancer-chemopreventive compounds: from signaling and gene expression to pharmacological effects
Section snippets
Chemoprevention and carcinogenesis
Cancer development is a long-term process that appears to proceed by step-by-step carcinogenesis events that ultimately spread from one area of the body to other parts of the body during the late metastasis stage. Current clinical therapies of cancer, which include surgery, radiation and chemotherapy, are limited, particularly during the terminal metastasis phase. However, there is increasing evidence from cancer epidemiological and pathological studies suggesting that many human cancers could
Inducers of detoxifying enzymes as blocking agents in chemoprevention
The drug-metabolizing enzyme system comprises phase I (oxidation, reduction and hydrolysis) and phase II (glucuronidation, sulfation, acetylation, methylation, and conjugation with glutathione) enzymes. These enzymes can be categorized as activating or detoxifying enzymes based on their metabolic activities towards the production or detoxification of carcinogens. Physiological balances between these enzymes, including their levels of expression and potential genetic polymorphism, might dictate
Apoptosis and cell-cycle arrest induced by suppressing agents in chemoprevention
Generally, the growth rate of pre-neoplastic or neoplastic cells outpace that of normal cells because of malfunctioning or dysregulation of their cell-growth and cell-death machineries [50]. Therefore, induction of apoptosis or cell-cycle arrest by dietary chemopreventive compounds can be an excellent approach to inhibit the promotion and progression of carcinogenesis and to remove genetically damaged, pre-initiated or neoplastic cells from the body (Figure 2).
Challenges of potential application of dietary chemopreventive compounds in humans
To successfully translate the above in vitro signaling and gene-expression events obtained in cell culture systems and animal models to beneficial pharmacological effects in humans, several other obstacles and challenges remain to be overcome. First, defining the target population remains one of the fundamental questions in human chemoprevention trials. It appears that the significant mechanistic differences that exist between inducers of detoxifying enzymes and anti-proliferative agents
Concluding remarks
Dietary chemopreventive compounds offer great potential in the fight against cancer by inhibiting the carcinogenesis process through the regulation of cell-defensive and cell-death machineries. To block the initiation of carcinogenesis, enhancement of the detoxifying and antioxidant enzyme system for efficient neutralization and elimination of endogenous or exogenous carcinogenic species provides a good starting point, particularly for the high-risk populations exposed to environmental
Acknowledgements
We thank all the members of the A-N.T.K. laboratory for their helpful discussions. We apologize for not being able to cite many important publications in this emerging field because of space constraints. Work described here was supported in part by grants R01-CA073674, R01-CA092515 and R01-CA094828 from the National Institutes of Health (NIH).
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