Evidence of a novel docetaxel sensitizer, garlic-derived S-allylmercaptocysteine, as a treatment option for hormone refractory prostate cancer.

The recent introduction of docetaxel in the treatment of hormone refractory prostate cancer (HRPC) has made a small but significant impact on patient survival. However, its effect is limited by intolerance and resistance. The aim of our study was to investigate if the garlic-derived compound, S-allylmercaptocysteine (SAMC), was able to act as a docetaxel sensitizing agent. First, the effect of SAMC on docetaxel sensitivity was examined on 3 HRPC cell lines by colony forming assay. We found that SAMC increased the efficacy of docetaxel on colony forming inhibition by 9-50% compared to single agent treatment. Second, using the HRPC CWR22R nude mice model, we found that the combination of SAMC and docetaxel was 53% more potent than docetaxel alone (p = 0.037). In addition, there was no additive toxicity in the mice treated with the combination therapy evidenced by histological and functional analysis of liver, kidney and bone marrow. These results suggest that SAMC is able to increase the anticancer effect of docetaxel without causing additional toxic effect in vivo. Third, flow cytometry and Western blotting analysis on HRPC cell lines demonstrated that SAMC promoted docetaxel-induced G2/M phase cell cycle arrest and apoptotic induction. In addition, immunohistochemistry on CWR22R xenograft revealed a suppression of Bcl-2 expression and upregulation of E-cadherin in the SAMC and docetaxel treated animals. These results suggest that SAMC may promote docetaxel-induced cell death through promoting G2/M cell cycle arrest and apoptosis. Our study implies a potential role for SAMC in improving docetaxel based chemotherapy for the treatment of HRPC.

Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer.

The presence of circulating tumor cells (CTC) is common in prostate cancer patients, however until recently their clinical significance was unknown. The CTC stage is essential for the formation of distant metastases, and their continuing presence after radical prostatectomy has been shown to predict recurrent or latent disease. Despite their mechanistic and prognostic importance, due both to their scarcity and difficulties in their isolation, little is known about the characteristics that enable their production and survival. The aim of this study was to investigate the molecular mechanisms underlying the survival of CTC cells. A novel CTC cell line from the bloodstream of an orthotopic mouse model of castration-resistant prostate cancer was established and compared with the primary tumor using attachment assays, detachment culture, Western blot, flow cytometry and 2D gel electrophoresis. Decreased adhesiveness and expression of adhesion molecules E-cadherin, beta4-integrin and gamma-catenin, together with resistance to detachment and drug-induced apoptosis and upregulation of Bcl-2 were integral to the development of CTC and their survival. Using proteomic studies, we observed that the GRP94 glycoprotein was suppressed in CTC. GRP94 was also shown to be suppressed in a tissue microarray study of 79 prostate cancer patients, indicating its possible role in prostate cancer progression. Overall, this study suggests molecular alterations accounting for the release and survival of CTC, which may be used as drug targets for either anti-metastatic therapy or the suppression of latent disease. We also indicate the novel involvement of GRP94 suppression in prostate cancer metastasis.

Garlic-derived S-allylmercaptocysteine is a novel in vivo antimetastatic agent for androgen-independent prostate cancer.

PURPOSE: There is epidemiologic evidence that high garlic consumption decreases the incidence of prostate cancer, and compounds isolated from garlic have been shown to have cancer-preventive and tumor-suppressive effects. Recent in vitro studies in our laboratory have shown that garlic-derived organosulfur compound S-allylmercaptocysteine suppresses invasion and cell motility of androgen-independent prostate cancer cells via the up-regulation of cell-adhesion molecule E-cadherin. S-allylmercaptocysteine is therefore a potential antimetastatic drug with broad clinical applications that we tested in vivo for the first time in this study. EXPERIMENTAL DESIGN: We used a newly established fluorescent orthotopic androgen-independent prostate cancer mouse model to assess the ability of S-allylmercaptocysteine to inhibit tumor growth and dissemination. RESULTS: We showed that oral S-allylmercaptocysteine not only inhibited the growth of primary tumors by up to 71% (P < 0.001) but also reduced the number of lung and adrenal metastases by as much as 85.5% (P = 0.001) without causing notable toxicity. This metastatic suppression was accompanied by a 91% reduction of viable circulating tumor cells (P = 0.041), suggesting that S-allylmercaptocysteine prevents dissemination by decreasing tumor cell intravasation. CONCLUSIONS: Our results provide in vivo evidence supporting the potential use of S-allylmercaptocysteine as an E-cadherin up-regulating antimetastatic agent for the treatment of androgen-independent prostate cancer. This is the first report of the in vivo antimetastatic properties of garlic, which may also apply to other cancer types.

Outcomes among patients requiring unplanned intra-aortic balloon pump reinsertion in cardiogenic shock.

INTRODUCTION: The intra-aortic balloon pump (IABP) is the most frequently utilized form of temporary mechanical circulatory support (MCS) in cardiogenic shock (CS). Withdrawal of IABP support may precipitate hemodynamic compromise such that IABP reinsertion is required. Data are scarce regarding the incidence and outcomes of patients undergoing IABP reinsertion in this setting. METHODS: In this single-center retrospective study, we identified consecutive patients with CS in whom IABP reinsertion was required for hemodynamic decompensation. These patients were compared to matched controls in whom IABP withdrawal was successful. The primary outcome measure was in-hospital mortality, while the secondary outcome measure was a composite of in-hospital death, need for advanced MCS or heart transplantation, or discharge to hospice. RESULTS: Among 222 patients requiring IABP for CS, we identified 20 case patients (incidence=9.0%) and 38 matched controls. Baseline characteristics were similar for the two groups. In-hospital mortality was 70% in the reinsertion group and 31% in the controls (Odds ratio (OR) 5.2, 95% CI 1.4-18.9, P=0.005). The composite secondary endpoint was also significantly more common in the reinsertion group than the controls (85% vs. 42%; OR 7.3, 95% CI 1.6-33.1, P=0.002). On multivariate analysis, the need for IABP reinsertion was independently associated with in-hospital mortality (OR 7.7, 95% CI 1.6-36.2, P=0.01). CONCLUSION: Among patients with CS undergoing IABP removal, hemodynamic deterioration requiring IABP reinsertion is associated with extremely poor outcomes and, in appropriate patients, should prompt consideration of more advanced cardiac support.

Clinical implications of thrombocytopenia among patients undergoing intra-aortic balloon pump counterpulsation in the coronary care unit.

BACKGROUND: Thrombocytopenia Hypothesis: intra-aortic balloon pump (IABP)-associated thrombocytopenia is not associated with an increased risk of major bleeding or in-hospital death. Thrombocytopenia is a common adverse effect of the IABP. However, the clinical implications of IABP-associated thrombocytopenia are unknown. METHODS: We assessed the incidence and predictors of thrombocytopenia, and the association between thrombocytopenia and relevant clinical end points, using prospectively collected data on 252 consecutive patients undergoing IABP in a single coronary care unit (CCU). RESULTS: Anticoagulation with intravenous heparin was administered to 182 patients (72%). Baseline platelet counts were 232 000 +/- 96 000 mL, decreased to 154 000 +/- 74 000 mL at day 3, and recovered to baseline by day 8. Thrombocytopenia (nadir < 150 000 mL or > 50% reduction from baseline) occurred in 109 patients (43%), with a similar incidence among patients who received heparin and those who did not (45% vs 40%, P = 0.5). Independent predictors of thrombocytopenia were lower body weight, cardiogenic shock, and duration of IABP support. The incidence of both major bleeding and in-hospital death were higher among patients who developed thrombocytopenia than among those who did not (13.8% vs 4.2%, P = 0.01 and 28% vs 16%, P = 0.02, respectively). However, after controlling for confounding variables, thrombocytopenia was not an independent predictor of either major bleeding (odds ratio [OR]: 2.2, 95% confidence interval [CI]: 0.8-6.4, P = 0.1) or in-hospital death (OR: 1.5, 95% CI: 0.8-2.9, P = 0.3). CONCLUSIONS: Among patients undergoing IABP in the CCU, thrombocytopenia is generally mild, appears to be unrelated to concomitant heparin use, and is not associated with an increased risk of major bleeding or in-hospital death.