Ingestion of an isothiocyanate metabolite from cruciferous vegetables inhibits growth of human prostate cancer cell xenografts by apoptosis and cell cycle arrest

Abstract

Epidemiological surveys indicate that intake of cruciferous vegetables is inversely related to prostate cancer incidence, although the responsible dietary factors have not been identified. Our studies demonstrated that exposure of human prostate cancer cells in culture to the N-acetylcysteine (NAC) conjugate of phenethyl isothiocyanate (PEITC-NAC), the major metabolite of PEITC that is abundant in watercress, inhibited proliferation and tumorigenesis. The PEITC-NAC is known to mediate cytoprotection at initiation of carcinogenesis. The relevance of PEITC-NAC in diets on the growth of prostate tumor cells has been evaluated in immunodeficient mice with xenografted tumors of human prostate cancer PC-3 cells. The daily PEITC-NAC (8 micromol/g) supplemented diet group showed a significant reduction in tumor size in 100% of the mice during the 9-week treatment period. Tumor weight at autopsy was reduced by 50% compared with mice on the diet without PEITC-NAC (P = 0.05). Mitosis and in vivo 5-bromo-2'-deoxyuridine labeled proliferating cells were reduced in these tumors. The PEITC-NAC diet up-regulated the inhibitors of cyclin-dependent kinases p21WAF-1/Cip-1 and p27Kip1, and reduced the expression of cyclins D and E, indicating they were potential molecular targets. As a result, phosphorylated Rb was significantly decreased and the G1- to S-phase transition retarded. The treated tumors also showed a significant increase in apoptosis as determined by in situ end-labeling, and by poly ADP-ribose polymerase cleavage. This study demonstrates the first in vivo evidence of dietary PEITC-NAC inhibiting tumorigenesis of prostate cancer cells. PEITC-NAC may prevent initiation of carcinogenesis and modulate the post-initiation phase by targeting cell cycle regulators and apoptosis induction.

Phenylhexyl isothiocyanate inhibits histone deacetylases and remodels chromatins to induce growth arrest in human leukemia cells

“…Our lab has reported that phenethyl isothiocyanate and sulforaphane induce growth arrest and apoptosis in prostate cancer cells in culture, as well as in xenografted tumors in immunodeficient mice, suggesting that they act also at the post-initiation progression stages (8,9). Isothiocyanates have been further reported to induce JNK-MAP kinases, p53-mediated apoptosis and cdk-mediated cell cycle arrest in different types of cancer cells (10)(11)(12)(13).…”

Direct Modification of the Proinflammatory Cytokine Macrophage Migration Inhibitory Factor by Dietary Isothiocyanates

“…They can act in a chemopreventive capacity via inhibition of carcinogen-activating phase I enzymes (1) and induction of phase II detoxification enzymes (2). Isothiocyanates are also active in the post-initiation phase of tumorigenesis and are, therefore, proposed to have chemotherapeutic potential (3,4). Isothiocyanate-mediated disruption of cancer progression is achieved by a variety of mechanisms including modulation of cell growth (5), inhibition of angiogenesis (6), suppression of metastasis (7), and induction of apoptosis (8,9).…”

“…An amine linker was added to phenethyl isothiocyanate (PEITC) 3 without compromising cytotoxicity, and the molecule was immobilized to a solid phase resin. The pleiotropic cytokine macrophage migration inhibitory factor (MIF) was identified as a major biological target of PEITC.…”

Antimutagenic Effect of Phenethyl Isothiocyanate

“…Antimutagenic and anticarcinogenic effects of PEITC are caused by the influence on a metabolic activation of mutagen by the inhibition of the level and/or activity of CYP enzymes and also by the effect on detoxification enzymes (15,29,40). PEITC has also the antiproliferative effect and induces apoptosis (24,41,42). Described bacteriotoxic effect of ITCs (24,43) suggests that the stimulation of apoptosis by chemopreventive agents may often reflect occurrence of toxic effects at high doses.…”