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Cancer chemoprevention with dietary phytochemicals

Key Points

  • Many population-based studies have highlighted the ability of macronutrients and micronutrients in vegetables and fruit to reduce the risk of cancer. Recently, attention has been focused on phytochemicals — non-nutritive components in the plant-based diet that possess cancer-preventive properties.

  • Despite remarkable progress in our understanding of the carcinogenic process, the mechanisms of action of most chemopreventive phytochemicals have not been fully elucidated.

  • Chemopreventive phytochemicals can block initiation or reverse the promotion stage of multistep carcinogenesis. They can also halt or retard the progression of precancerous cells into malignant ones.

  • Many molecular alterations associated with carcinogenesis occur in cell-signalling pathways that regulate cell proliferation and differentiation. One of the central components of the intracellular-signalling network that maintains homeostasis is the family of mitogen-activated protein kinases (MAPKs).

  • Numerous intracellular signal-transduction pathways converge with the activation of the transcription factors NF-κB and AP1. As these factors mediate pleiotropic effects of both external and internal stimuli in the cellular-signalling cascades, they are prime targets of diverse classes of chemopreventive phytochemicals.

  • Basic helix–loop–helix transcription factors such as NRF2 regulate expression of phase II enzymes, which detoxify carcinogens and protect against oxidative stress. A number of phytochemicals have been shown to induce expression of phase II enzymes via NRF2.

  • β-Catenin, a multifunctional protein that was originally identified as a component of cell–cell adhesion machinery, is another important molecular target for chemoprevention. Several dietary phytochemicals have been shown to target this molecule.

Abstract

Chemoprevention refers to the use of agents to inhibit, reverse or retard tumorigenesis. Numerous phytochemicals derived from edible plants have been reported to interfere with a specific stage of the carcinogenic process. Many mechanisms have been shown to account for the anticarcinogenic actions of dietary constituents, but attention has recently been focused on intracellular-signalling cascades as common molecular targets for various chemopreventive phytochemicals.

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Figure 1: Dietary phytochemicals that block or suppress multistage carcinogenesis.
Figure 2
Figure 3: Effect of phytochemicals on activation of NF-κB and AP1.
Figure 4: Transcriptional activation by NRF2.
Figure 5: Effect of phytochemicals on β-catenin signalling.

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Acknowledgements

The author thanks the members of his laboratory, especially H.K. Na, J.K. Kundu, K.S. Chun, J.S. Lee, M.H. Chung, E. Kim and J.M. Lee (currently at the University of Wisconsin-Madison) for having prepared the table and illustrations, as well as sorting out the references. Work in the author's laboratory is supported by research grants from the Korea Institute of Science and Technology Evaluation and Planning (KISTEP) for functional food research and development, Ministry of Science and Technology.

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DATABASES

LocusLink

β-catenin

AKT

APAF1

APC

CBP

CKI

COX2

Egf

ERBB2

ERK2

FOS

GSK-3β

GST

HO-1

HRAS

IκB

JNK

JUN

KEAP1

NF-κB

NRF1

NRF2

p300

p38

p53

PI3K

PKC

STAT3

TNF-α

VEGF

WAF1

γ-GCS

FURTHER INFORMATION

1997 World Cancer Research Fund and AICR report

'Five A Day for Better Health' report

Glossary

LUCIFERASE-REPORTER-GENE ASSAY

A recombinant method that is used to measure transcriptional activity in which the regulatory sequence (for example, promoter or enhancer) of interest is joined to a firefly luciferase gene that, following activation, produces light from luciferin in the presence of ATP added to the assay mixture. The relative intensity of the light emission is measured with a luminometer.

CREB

(Cyclic AMP response element binding protein). CREB is a leucine zipper transcription factor that binds to DNA at the cyclic AMP response element (CRE) as a homo- or heterodimer. It has pivotal roles in the control of cellular proliferation and differentiation, apoptosis, intermediary metabolism, inflammation and numerous other responses, particularly in hepatocytes, adipocytes and haematopoietic cells.

PHASE II ENZYMES

A group of xenobiotic metabolizing enzymes that are mainly involved in the inactivation and excretion of carcinogens and other toxic chemical substances.

ANTIOXIDANT-RESPONSIVE ELEMENT

(ARE). A specific DNA-promoter-binding region that can be transcriptionally activated by numerous antioxidants and/or electrophiles. Many stress-response genes encoding phase II detoxification or antioxidant enzymes such as glutathione S-transferase, quinone reductase, and heme oxygenase-1 — which provide defence against cellular oxidative stress — have this element in their 5′-flanking region to facilitate the transcription process.

REDOX CYCLING

A reciprocal transformation between an oxidant and its reductive counterpart. An example is conversion of catechol to quinone via semiquinone or vice versa.

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Surh, YJ. Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 3, 768–780 (2003). https://doi.org/10.1038/nrc1189

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