Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer.

Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with docetaxel for uptake by the drug transporter OATP1B3. Irrespective of docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by docetaxel treatment in vivo. These results indicate that to optimise docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with docetaxel in CRPC.

Combined lycopene and vitamin E treatment suppresses the growth of PC-346C human prostate cancer cells in nude mice.

Epidemiologic studies have repeatedly associated a high intake of lycopene and vitamin E with reduced prostate cancer risk. The present study examined the ability of the 2 compounds to reduce tumor growth and prostate-specific antigen (PSA) plasma levels in the PC-346C orthotopic mouse model of human prostate cancer. Three days after intraprostatic tumor injection, NMRI nu/nu mice were administered a daily oral dose of synthetic lycopene [5 or 50 mg/kg body weight (BW)], vitamin E in the form of alpha-tocopheryl acetate (5 or 50 mg/kg BW), a mixture of lycopene and vitamin E (5 mg/kg BW each), or vehicle. Intraprostatic tumor volume and plasma PSA concentrations were measured at regular intervals. Mice were killed when the tumor load exceeded 1000 mm(3) or on d 95 when the study was terminated. Prostate and liver were analyzed by HPLC for lycopene isomers and alpha- and gamma, delta-tocopherol concentrations. None of the single treatments significantly reduced tumor volume. In contrast, combined treatment with lycopene and vitamin E, at 5 mg/kg BW each, suppressed orthotopic growth of PC-346C prostate tumors by 73% at d 42 (P < 0.05) and increased median survival time by 40% from 47 to 66 d (P = 0.02). The PSA index (PSA:tumor volume ratio) did not differ between experimental groups, indicating that PSA levels were not selectively affected. Lycopene was detected only in mice supplemented with lycopene. As in humans, most tissue lycopene was in the cis-isomer conformation, whereas 77% trans-lycopene was used in the dosing material. Liver alpha-tocopherol concentrations were increased in mice supplemented with both 50 mg/kg (226%, P < 0.05) and 5 mg/kg vitamin E (41%, P < 0.05), whereas prostate alpha-tocopherol concentrations were increased only by the higher dose (83%, P < 0.05). Our data provide evidence that lycopene combined with vitamin E may inhibit the growth of prostate cancer and that PSA can serve as a biomarker of tumor response for this treatment regimen.