Chemoprotection by sulforaphane: keep one eye beyond Keap1

Abstract

Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables, with particularly high levels detected in broccoli and broccoli sprouts. Over a decade ago, this phytochemical was identified as a likely chemopreventive agent based on its ability to induce Phase 2 detoxification enzymes, as well as to inhibit Phase 1 enzymes involved in carcinogen activation. Considerable attention has focused on SFN as a 'blocking' agent, with the ability to modulate the Nrf2/Keap1 pathway, but recent evidence suggests that SFN acts by numerous other mechanisms. SFN induces cell cycle arrest and apoptosis in cancer cells, inhibits tubulin polymerization, activates checkpoint 2 kinase, and inhibits histone deacetylase activity. The latter findings suggest that SFN may be effective during the post-initiation stages of carcinogenesis, as a 'suppressing' agent. Moreover, pharmacological administration of SFN may be a promising therapeutic approach to the treatment of cancers, including those characterized by increased inflammation and involving viral or bacterial-related pathologies. The present review discusses the more widely established chemoprotective mechanisms of SFN, but makes the case for additional work on mechanisms that might be of importance during later stages of carcinogenesis, beyond Keap1.

Fig. 1

Increasing interest in SFN, based on annual citations in PubMed.

Fig. 2

SFN acts at various steps during multi-stage carcinogenesis. This figure illustrates the various ‘blocking’ and ‘suppressing’ mechanisms by which SFN inhibits multi-stage carcinogenesis. Each of the protective mechanisms (1–6) is described in further detail in the text. Adapted from a previous review [5].

Fig. 3

SFN induces ARE expression through disruption of the Keap1–Nrf2 complex. SFN can interact directly with sulfhydryl residues on Keap1, causing Nrf2 to be released. Alternatively, SFN can activate the MAPK pathway, causing phosphorylation of Keap1 and release of Nrf2. Once released, Nrf2 enters the nucleus, where it transactivates ARE-responsive genes.

Fig. 4

Multiple mechanisms of chemoprotection by SFN. This figure combines empirically tested as well as postulated activities of SFN, based largely on in vitro studies, plus in vivo findings where available. Each of the protective mechanisms is described in further detail in the text.