Epidemiological studies have revealed an inverse correlation between dietary intake of cruciferous vegetables and the risk of different malignancies including cancer of the prostate. Cancer chemopreventive effects of cruciferous vegetables are attributed to isothiocyanates (e.g., sulforaphane; SFN), which are generated upon processing (cutting or chewing) of these vegetables. However, the mechanism for cancer chemoprevention by isothiocyanates, including SFN, is poorly defined. In the present study, we tested the hypothesis that SFN administration affects immune function using TRAMP model. The SFN treatment caused apoptosis in cultured prostate cancer cells derived from spontaneously developing tumor of a TRAMP mouse (TC-1) as revealed by cytoplasmic histone-associated DNA fragmentation and appearance of sub-diploid cells. The SFN-induced apoptosis in TC-1 cells correlated with induction of multi-domain pro-apoptotic protein Bax and down-regulation of Bcl-xL expression. Male TRAMP mice (6-weeks old) were verified for transgene expression by RT-PCR and then divided into 2 groups (6 mice/group). The experimental group of mice was orally gavaged with 1 mg SFN (in 0.1 ml PBS) three times per week for 13 weeks, while the control group of mice received PBS. This study was not sufficiently powered to determine the effect of SFN administration on prostate cancer incidence, burden or progression, rather designed to determine immunomodulatory properties of SFN. Analyses of the cytokine release by mature dendritic cells (DC) cultured from bone marrow of control and treated mice showed a significant increase in release of interleukin 12 (IL-12), a natural killer (NK) cell activator and Th1 regulator, in SFN treated mice. Similarly, release of tumor necrosis factor alpha (TNFα), a major pro-inflammatory cytokine, was elevated in cultures of IL-2 activated NK cells derived from the spleen of SFN treated mice in comparison to controls. The wet spleen weight did not differ between control and SFN treated mice. The SFN-mediated effect also resulted in a higher level of cytotoxicity of IL-2 activated NK cells towards TC-1 target cells. Further, NK:DC co-culture using cells from control and treated mice resulted in elevated cell-mediated cytotoxicity against TC-1 target cells using effector cells from SFN treated mice. These results show, for the first time, that oral administration of SFN stimulates cancer cell immunity mediated by DC and NK cells in a spontaneously developing mouse model of prostate cancer. These results provide a strong rationale for testing chemopreventive efficacy of SFN in TRAMP model. This study was supported by the NCI grant CA115498.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA