Abstract 5395: Phenethyl isothiocyanate sensitizes androgen-independent human prostate cancer cells to Docetaxel-induced apoptosis in vitro and in vivo

Phenethyl isothiocyanate (PEITC), a constituent of edible cruciferous vegetables such as watercress, not only affords significant protection against chemically-induced cancer in experimental animals but also suppresses growth of cancer cells in culture and in vivo. The present study demonstrates, for the first time, that PEITC is highly effective in sensitizing PC-3 and DU145 androgen-independent human prostate cancer cells to Docetaxel-induced apoptosis in vitro as well as in vivo. Pharmacologic concentrations of PEITC (1 and 2 µmol/L) synergistically increased cytotoxicity of Docetaxel in PC-3 and DU145 cells as judged by trypan blue dye exclusion assay and Sulforhodamine B assay. The PEITC-mediated sensitization of growth inhibition by Docetaxel was associated with increased apoptosis (judged by DAPI assay and analysis of cytoplasmic histone-associated DNA fragmentation), suppression of anti-apoptotic proteins Bcl-2 and XIAP, and induction of multidomain proapoptotic proteins Bax and Bak. Moreover, the HCT-116 human colon cancer cells lacking XIAP protein were significantly more sensitive to growth inhibition and apoptosis induction by the PEITC-Docetaxel combination compared with parental HCT-116 cells. The PEITC-Docetaxel combination was markedly more efficacious against PC-3 xenografts in vivo compared with PEITC or Docetaxel alone. For example, the average tumor volume on last day of measurement (day 38) in mice treated with PEITC-Docetaxel combination (564 ± 114 mm 3 ) was significantly lower compared with control mice [gavaged with 0.1 mL phosphate-buffered saline (PBS) five times per week and 0.1 mL PBS on day 15, 22 and 29 after tumor cell implantation; n= 6; 1071 ± 148 mm 3 ; P= 0.019 by two-tailed Student9s t-test], PEITC alone treated mice (6 μmol PEITC in 0.1 mL PBS by garage five times per week; n= 7; 1043 ± 71 mm 3 ; P= 0.004), and Docetaxel alone treated mice (5 mg Docetaxel/kg body weight by intraperitoneal injection on day 15, 22 and 29 after tumor cell implantation; n= 6; 931 ± 126 mm 3 ; P= 0.053). Consistent with cellular data, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay revealed significantly higher count of apoptotic bodies in tumor sections from mice treated with the PEITC-Docetaxel combination compared with PEITC or Docetaxel alone treatment groups. Moreover, the PEITC and/or Docetaxel-mediated changes in the levels of apoptosis regulating proteins in the tumor were generally consistent with the alterations observed in cultured cells. The results of the present study offer obligatory impetus to test PEITC-Docetaxel combination for the treatment of androgen-independent prostate cancer in a clinical setting. This investigation was supported by the National Cancer Institute grant 2 RO1 CA101753-06. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5395.