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

• Published in: International journal of cancer Vol. 122; no. 9; pp. 1941 - 1948
• Main Authors: Howard, Edward W., Lee, Davy T., Chiu, Yung Tuen, Chua, Chee Wai, Wang, Xianghong, Wong, Yong Chuan
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.05.2008; Wiley-Liss
• Subjects: Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Cadherins - metabolism; Cell Division - drug effects; Cell Line, Tumor; Chemotherapy; combination chemotherapy; Cysteine - adverse effects; Cysteine - analogs & derivatives; Cysteine - pharmacology; docetaxel; Down-Regulation - drug effects; Drug Synergism; Flow Cytometry; G2 Phase - drug effects; Garlic; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunohistochemistry; Male; Medical sciences; Mice; Mice, Nude; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Pharmacology. Drug treatments; prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; S‐allylmercaptocysteine; Taxoids - adverse effects; Taxoids - pharmacology; Transplantation, Heterologous; Tumor Stem Cell Assay; Tumors; Up-Regulation - drug effects; Antineoplastic agent; Cysteine; Prostate disease; Hormone therapy; Urology; Cancerology; Taxane derivatives; Established cell line; Antimitotic; Male genital diseases; Human; Thiol; Drug combination; Treatment resistance; Urinary system disease; Rodentia; Docetaxel; combination chemotherapy; Malignant tumor; S-allylmercaptocysteine; In vitro; Sulfur containing aminoacid; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Aminoacid; Animal; Garlic; Combined treatment; Prostate cancer; Chemosensitizing agent; Cancer
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.23355

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. © 2008 Wiley‐Liss, Inc.