In vitro and in vivo effects of bicalutamide on the expression of TrkA and P75 neurotrophin receptors in prostate carcinoma.
BACKGROUND
Neurotrophine tyrosine kinase receptors (NTR) are expressed in prostate carcinoma (PCa), and their distribution seems to be related to disease malignancy.


METHODS
In this article we analyzed the expression of NTRK1 (TrkA), NTRK2 (TrkB), NTRK3 (TrkC), and p75NTR in a 102 patient cohort with clinically localized tumors, which had been surgically treated with radical prostatectomy (RP). Among these, 61 patients received RP as sole treatment, and 41 patients received neoadjuvant hormone therapy (NHT) for 120 days with bicalutamide 150 mg/day. In addition, we analyzed the NTR expression in vitro in the androgen receptor positive, androgen-sensitive cell strains derived from CWR22R.


CONCLUSIONS
We demonstrated that: (i) TrkA and TrkC levels were significantly upmodulated, whereas (ii) p75NTR seemed to be reduced, and (iii) TrkB expression seemed to be not affected by NHT. TrkA were constitutively activated when its levels were very high. In vitro studies showed that the dehydrotestosterone (DHT) was able to maintain low TrkA and TrkC protein levels. Conversely, DHT was able to maintain p75NTR at high levels. Bicalutamide treatment induced TrkA and TrkC and reduced p75NTR expression. Antiproliferative effects of CEP701 were dependent to TrkA levels. A therapeutical effect of CEP701 was seen in all culture conditions, and bicalutamide seemed to sensitize prostate cancer cells to the effects of a pan TrkA inhibitor CEP701, suggesting that a sequential therapy between these drugs could further increase the efficacy of Trk inhibition.
Festuccia
Claudio
C
Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy. festucci@univaq.it
Gravina
Giovanni Luca
GL
Muzi
Paola
P
Pomante
Roberto
R
Ventura
Luca
L
Ricevuto
Enrico
E
Vicentini
Carlo
C
Bologna
Mauro
M
D000328:Adult; D000368:Aged; D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000813:Anilides / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D002227:Carbazoles / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D045744:Cell Line, Tumor; D015331:Cohort Studies; D013196:Dihydrotestosterone / Q000494:pharmacology; D005663:Furans; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020800:Receptor, Nerve Growth Factor / Q000096:biosynthesis*; D020917:Receptor, trkA / Q000096:biosynthesis*; D020812:Receptor, trkC / Q000096:biosynthesis; D014105:Tosyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use
D000726:Androgen Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D002227:Carbazoles; D005663:Furans; D007211:Indoles; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D020800:Receptor, Nerve Growth Factor; D014105:Tosyl Compounds; D013196:Dihydrotestosterone; C053541:bicalutamide; C119379:lestaurtinib; D020917:Receptor, trkA; D020812:Receptor, trkC