1. ARE ARE Prostate cancer cell Prostate cancer cell
A Castration-resistant prostate cancer growth
B agents targeting castration-resistant prostate cancer
Testis
Adrenal gland
GnRH
Androgen (A)
Androgen (A)
Adrenal gland
Testis
CYP17
inhibitors
Prostate cancer
cell
Abiraterone
TAK-700 TOK-001
GnRH
agonists / antagonists or castration AR
AR Antagonist
MDV-3100
ARN-509
EZN-4176
AR antisense AR AR
AR Antagonist
Androgen (A)
Androgen (A)
EPR-001
AR modulator AR
AR nuclear transport inhibitor
hsp-27 AR
Prostate cancer
cell
ODM-201
Androgen (A) AR A
hsp-27
degradation AR AR
hsp antisense
ARE
ARE
OGX-427 AR AR
hsp-27
ARE AR A
Androgen (A)
ARE
Growth arrest AR
Fig.1. (A) Prostate cancer cell growth in the presence of castration can be maintained through intra- tumoral or adrenal production of androgen (light blue box), by overexpression of wt-AR (rectanglular blue box) or mutated/alternatively-spliced AR (oval blue box). Hsp-27 (red box) prevents degradation of cytoplasmatic unbound AR. Androgen-bound AR or mutated/spliced AR transports to the nucleus, binds to androgen responsive elements on the DNA, leading to AR-induced gene tanscription and cellular growth.
(B) Agents targeting CRPC include CYP17 inhibitors, AR antagonists, AR modulators, AR antisense molecules, AR nuclear transport inhibitors and heat-shock-protein antisense molecules (grey boxes). The generic names of the compounds currently evaluated in clinical trialsa re depicted in red.
ARE
AR-induced gene transcription
tumorigenesis