Molecular targets of dietary phenethyl isothiocyanate and sulforaphane for cancer chemoprevention

Abstract

Development of cancer is a long-term and multistep process which comprises initiation, progression, and promotion stages of carcinogenesis. Conceivably, it can be targeted and interrupted along these different stages. In this context, many naturally occurring dietary compounds from our daily consumption of fruits and vegetables have been shown to possess cancer preventive effects. Phenethyl isothiocyanate (PEITC) and sulforaphane (SFN) are two of the most widely investigated isothiocyanates from the crucifers. Both have been found to be very potent chemopreventive agents in numerous animal carcinogenesis models as well as cell culture models. They exert their chemopreventive effects through regulation of diverse molecular mechanisms. In this review, we will discuss the molecular targets of PEITC and SFN potentially involved in cancer chemoprevention. These include the regulation of drug-metabolizing enzymes phase I cytochrome P450s and phase II metabolizing enzymes. In addition, the signaling pathways including Nrf2-Keap 1, anti-inflammatory NFkappaB, apoptosis, and cell cycle arrest as well as some receptors will also be discussed. Furthermore, we will also discuss the similarities and their potential differences in the regulation of these molecular targets by PEITC and SFN.

Fig. 1

Chemical structures of PEITC and SFN. Both PEITC and SFN are isothiocyanates, which are characterized by sulfur containing N=C=S functional group

Fig. 2

Potential molecular pathways targeted by PEITC and SFN. PEITC and SFN affect various molecular targets and pathways, including phases I and II DME, NFκB, cell cycle arrest, apoptosis, and receptors

Fig. 3

Molecular targets in Nrf2/phase II enzymes pathway modulated by PEITC and SFN. In unstimulated cells, Keap 1 sequesters Nrf2 and bridges it to Cul-3-dependent ubiquitinase for ubiquitination. The ubiquitinated Nrf2 is then targeted for proteosomal degradation. Both PEITC and SFN can activate Nrf2, although through different mechanisms. PEITC activates Nrf2 through activation of MAPK pathway while SFN modifies thiol group of Keap1 and releases Nrf2 from Keap1 binding

Fig. 4

Molecular targets in NFκB pathway modulated by PEITC and SFN. Inactivation of NFκB by PEITC and SFN is considered as one important chemopreventive mechanism. NFκB is normally sequestrated by IκB which is subjected to phosphorylation by IκK. Phosphorylation of IκB by IκK increases degradation of IκB and, therefore, increases nuclear translocation of NFκB. Both PEITC and SFN have been shown to inhibit activation of NFκB through inhibiting IκK. In addition, SFN have been shown to decrease DNA binding ability of NFκB

Fig. 5

Molecular targets in apoptosis and cell cycle arrest pathways modulated by PEITC and SFN. Although both PEITC and SFN are potent inducers of apoptosis, the initial signal that triggers apoptosis has been suggested to be different. SFN increases ROS generation and disrupts mitochondrial membrane potential, which leads to cytosolic release of cytochrome c and apoptosis. On the other hand, PEITC binds to tubulin, increases the cleavage of caspases 8 and 9, and triggers apoptosis. Both PEITC and SFN activate Chk2 and inactivate Cdk1, leading to cell cycle arrest. Cyclins A, D, and E are also downregulated by PEITC