Cancer chemoprevention: current state of the art

Abstract

The aim of cancer chemoprevention is disruption or delay of the molecular pathways that lead to carcinogenesis. Chemopreventive blocking and/or suppressing agents disrupt the molecular mechanisms that drive carcinogenesis such as DNA damage by reactive oxygen species, increased signal transduction to NF-κB, epigenomic deregulation, and the epithelial mesenchymal transition that leads to metastatic progression. Numerous dietary phytochemicals have been observed to inhibit the initiation phase of carcinogenesis, and therefore are useful in primary chemoprevention. Moreover, phytochemicals are capable of interfering with the molecular mechanisms of metastasis. Likewise, numerous synthetic compounds are relevant and clinically viable as chemopreventive agents during the fundamental stages of carcinogenesis. While molecularly targeted anti-cancer therapies are in constant stages of development, superior patient outcomes are observed if carcinogenic processes are prevented altogether. This article reviews the role of chemopreventive compounds in inhibition of cancer initiation and their ability to reduce cancer progression.

Keywords: blocking agents; chemoprevention; phytochemicals; suppressing agents.

Figure 1

Mechanism of Nrf2 signaling and activation of antioxidant gene expression. Nrf2 is sequestered in the cytoplasm by Keap1. In response to external stressors (eg oxidants and electrophiles), Nrf2 is released from Keap1 and translocates to the nucleus where it forms a heterodimer with Maf that binds to antioxidant-responsive elements (ARE). The Nrf2–Maf heterodimer increases transcription of genes downstream from the ARE that encode detoxifying and antioxidant enzymes such as GST and NQO1. These cytoprotective enzymes limit the effects of electrophiles and oxidants on DNA and help preserve genomic integrity. Abbreviations: Nrf2, NF-E2-related factor 2; Keap1, Kelch-like ECH-associating protein 1; GST, glutathione S-transferase; NQO1, NADPH: quinone oxidoreductase 1.