Epidemiological studies continue to support the premise that dietary intake of Allium vegetables such as garlic may reduce the risk of various types of malignancies including cancer of the prostate. Laboratory studies indicate that the anti-carcinogenic effect of Allium vegetables is due to organosulfur compounds, which are generated upon processing (e.g., cutting or chewing) of these vegetables. Garlic-derived compounds including diallyl sulfide, diallyl disulfide, and diallyl trisulfide (DATS) have been shown to afford significant protection against cancer in animal models induced by a variety of chemical carcinogens. For example, prevention of chemically-induced cancer by garlic compounds has been observed against benzo[a]pyrene-induced forestomach and pulmonary carcinogenesis in mice, N-nitrosomethylbenzylamine-induced esophageal cancer in rats, and azoxymethane-induced colon carcinogenesis in rats. We have shown previously that DATS significantly inhibits growth of androgen-independent human prostate cancer cell lines PC-3 and DU145 in vitro by causing cell cycle arrest and apoptosis induction. We now demonstrate that oral gavage of DATS (6 μmol DATS/mouse on Monday, Wednesday and Friday of each week), beginning on the day of tumor cell injection, significantly retards growth of PC-3 xenografts in nude mice. For instance, 20 days after starting therapy the average tumor volume in control mice was about 3-fold higher compared with DATS treated mice. Similarly, on day 15 the average tumor volume in DATS treated mice was approximately 55% lower compared with control mice. Average body weighs of the control and DATS treated mice did not differ significantly throughout the experimental protocol. Moreover, the DATS treated mice appeared healthy and did not exhibit any other signs of toxicity. Tumors from DATS treated mice exhibited a markedly higher count of apoptotic bodies compared with control tumors as judged by TUNEL assay. Consistent with the results in cultured PC-3 cells, DATS-mediated suppression of PC-3 xenograft growth correlated with induction of multidomain proapoptotic Bcl-2 family proteins Bax and Bak. Even though DATS treatment inhibited migration of cultured PC-3 cells, formation of new blood vessels was comparable in tumors of control and DATS treated mice as judged by immunohistochemistry for CD31. The present study indicates that DATS administration inhibits growth of PC-3 xenografts in vivo in association with induction of Bax and Bak. This study was supported by NCI grant CA113363.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA