Bicalutamide (Casodex)-induced prostate regression involves increased expression of genes encoding insulin-like growth factor binding proteins☆

Abstract 

Objectives. To examine the effects of bicalutamide (Casodex), a pure antiandrogen with high specificity for the androgen receptor, on insulin-like growth factor binding protein (IGFBP) expression and apoptotic regression of the rat ventral prostate.

Methods. Rats were treated daily with 10 mg/kg body weight bicalutamide or vehicle alone. Ventral prostates were collected at various days of treatment. Northern blot analysis was performed to quantitate expression of genes encoding IGFBPs, and the TUNEL method was used to determine the extent of apoptosis in ventral prostate.

Results. In rats treated daily with bicalutamide, increases in mRNA levels of IGFBP-2, -3, -4, and -5 were detectable by Northern blotting by 6 hours and reached 6 to 10-fold of control levels after 5 days of treatment. The time-course of induction of apoptosis in the ventral prostate by bicalutamide, as detected in situ by the TUNEL method, corresponded to the time-course of induction of IGFBP expression.

Conclusions. We demonstrate that apoptotic regression of the ventral prostate during bicalutamide treatment is accompanied by increased expression of IGFBP-2, -3, -4, and -5. Rapid induction of IGFBPs, which can limit access of insulin-like growth factors (IGFs) to the IGF-I receptor, may play a role in the induction of apoptosis by antiandrogens, particularly in view of the increasing evidence that IGF-I inhibits apoptosis. These results document a previously unrecognized effect of antiandrogens and extend our previous studies relating IGF physiology to prostate biology. Together with evidence that a strong positive correlation exists between plasma IGF-I levels and prostate cancer risk, our data suggest that IGF physiology may play a key role in prostate cancer biology and is strongly influenced by androgen-targeting therapies.