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.
Howard
Edward W
EW
Cancer Biology Group, Department of Anatomy, Faculty of Medicine, University of Hong Kong, Hong Kong.
Lee
Davy T
DT
Chiu
Yung Tuen
YT
Chua
Chee Wai
CW
Wang
Xianghong
X
Wong
Yong Chuan
YC
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003545:Cysteine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077143:Docetaxel; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D005737:Garlic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D043823:Taxoids / Q000009:adverse effects / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation / Q000187:drug effects
D015820:Cadherins; D019253:Proto-Oncogene Proteins c-bcl-2; C086300:S-allylmercaptocysteine; D043823:Taxoids; D000077143:Docetaxel; D003545:Cysteine