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

Abstract

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 5 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.

Anti-Cancer Effect of the Combination of Thiacremonone and Docetaxel by Inactivation of NF-κB in Human Cancer Cells

“…In addition, the combination of docetaxel, vinorelbine and oral estramustine was a well-tolerated regimen with high biochemical and objective response rates in patients with androgen-resistant prostate cancer (ARPC) (Rosenberg et al, 2009). Very similar to our finding, garlic-derived S-allylmercaptocysteine augmented docetaxel-induced effect on growth inhibition of cultured PC3 and DU145 cells, and this combination effect was greater and synergistic (Howard et al, 2008).…”

Gamma‐tocotrienol as an effective agent in targeting prostate cancer stem cell‐like population

“…1,2 Based on a previous study, the IC90 dosage of docetaxel for DU145 cells is 1.01 ng/mL. 33 However, in this study, 40 ng/mL of docetaxel was unable to induce any effect on the viability of the CSC-enriched population (Fig. 5).…”

“…5c). At a dosage of 40 ng/mL, which has been shown to induce apoptosis in DU145 cells, 33 docetaxel failed to induce any observable effect on prostasphere number, suggesting that CSC-enriched cells are highly resistant to docetaxel. However, c-T3 treatment was found to significantly decrease the spheroid number by more than 70% (Fig.…”

Naturally Occurring Organic Sulfur Compounds: An Example of a Multitasking Class of Phytochemicals in Anti-Cancer Research

“…A similar pattern of modulations has been frequently reconfirmed in the instance of xenograft mice models of hepatocellular carcinoma (Zhang, Z.M. et al, 2007) and refractory forms of prostate cancer (Howard et al, 2008;Singh et al, 2008).…”

“…The modulation of both cellular targets may be implicated in the chemosensitization to the same treatment. Studies on docetaxel, a chemotherapeutic administrated to patients affected by hormonal or colon cancers, show that both mechanisms may be implicated in the ability of OSCs to modulate its activity (Ban et al, 2009;Cox et al, 2006;Howard et al, 2008). Cox et al, however, have shown that coadministration of garlic and docetaxel did not significantly affect the drug disposition in breast cancer patients but a reduction of its clearance in specific cases cannot be excluded (Cox et al, 2006).…”