Sulforaphane inhibits prostate carcinogenesis and pulmonary metastasis in TRAMP mice in association with increased cytotoxicity of natural killer cells.
The present study shows that oral gavage of 6 mumol d,l-sulforaphane (SFN), a synthetic analogue of cruciferous vegetable-derived L isomer, thrice per week beginning at 6 weeks of age, significantly inhibits prostate carcinogenesis and pulmonary metastasis in TRAMP mice without causing any side effects. The incidence of the prostatic intraepithelial neoplasia and well-differentiated (WD) carcinoma were approximately 23% to 28% lower (P < 0.05 compared with control by Mann-Whitney test) in the dorsolateral prostate (DLP) of SFN-treated mice compared with controls, which was not due to the suppression of T-antigen expression. The area occupied by the WD carcinoma was also approximately 44% lower in the DLP of SFN-treated mice relative to that of control mice (P = 0.0011 by Mann Whitney test). Strikingly, the SFN-treated mice exhibited approximately 50% and 63% decrease, respectively, in pulmonary metastasis incidence and multiplicity compared with control mice (P < 0.05 by t test). The DLP from SFN-treated mice showed decreased cellular proliferation and increased apoptosis when compared with that from control mice. Additionally, SFN administration enhanced cytotoxicity of cocultures of natural killer (NK) cells and dendritic cells (DC) against TRAMP-C1 target cells, which correlated with infiltration of T cells in the neoplastic lesions and increased levels of interleukin-12 production by the DC. In conclusion, the results of the present study indicate that SFN administration inhibits prostate cancer progression and pulmonary metastasis in TRAMP mice by reducing cell proliferation and augmenting NK cell lytic activity.
Singh
Shivendra V
SV
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, USA. singhs@upmc.edu
Warin
Renaud
R
Xiao
Dong
D
Powolny
Anna A
AA
Stan
Silvia D
SD
Arlotti
Julie A
JA
Zeng
Yan
Y
Hahm
Eun-Ryeong
ER
Marynowski
Stanley W
SW
Bommareddy
Ajay
A
Desai
Dhimant
D
Amin
Shantu
S
Parise
Robert A
RA
Beumer
Jan H
JH
Chambers
William H
WH
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D003713:Dendritic Cells / Q000276:immunology; D017879:Isothiocyanates; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000276:immunology / Q000517:prevention & control*; D013454:Sulfoxides; D013861:Thiocyanates / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051028:bcl-2-Associated X Protein / Q000032:analysis
D020533:Angiogenesis Inhibitors; D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D013454:Sulfoxides; D013861:Thiocyanates; D051028:bcl-2-Associated X Protein; C016766:sulforaphane