Ingestion of an isothiocyanate metabolite from cruciferous vegetables inhibits growth of human prostate cancer cell xenografts by apoptosis and cell cycle arrest.
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.
Chiao
Jen Wei
JW
Department of Medicine, New York Medical College, Valhalla, NY 10595, USA. jen-wei_chao@nymc.edu
Wu
Hongyan
H
Ramaswamy
Gita
G
Conaway
C Clifford
CC
Chung
Fung-Lung
FL
Wang
Longgui
L
Liu
Delong
D
D000111:Acetylcysteine / Q000737:chemistry; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D017209:Apoptosis; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D002469:Cell Separation; D004396:Coloring Agents / Q000494:pharmacology; D056741:Cyclin D; D019927:Cyclin E / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D005434:Flow Cytometry; D016193:G1 Phase; D006801:Humans; D017879:Isothiocyanates / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008938:Mitosis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy; D016196:S Phase; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation; D014675:Vegetables / Q000378:metabolism*
D016588:Anticarcinogenic Agents; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D004396:Coloring Agents; D056741:Cyclin D; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017879:Isothiocyanates; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C058305:phenethyl isothiocyanate; D011065:Poly(ADP-ribose) Polymerases; D001973:Bromodeoxyuridine; D000111:Acetylcysteine