Abiraterone (CB-7598) inhibits 17 α-hydroxylase/C17, 20 lyase (CYP17A1) with an IC50 of 4 nM, an enzyme which is expressed in testicular, adrenal, and prostatic tumor tissues. Abiraterone was recently approved for the treatment of docetaxel-treated castration-resistant prostate cancer (CRPC), is often effective, but requires coadministration with glucocorticoids to curtail side effects. Abiraterone inhibited in vitro proliferation and AR-regulated gene expression of AR-positive prostate cancer cells, which could be explained by AR antagonism in addition to inhibition of steroidogenesis.
|Cell lines||PC-3 cells|
|Preparation method||Luciferase reporter assays We constructed a PSA-ARE3-luc luciferase reporter plasmid that was co-transfected with a human AR expression plasmid, F527-AR (wild-type (WT) or mutant as stated; mutations confirmed by sequencing (Beckman Coulter Genomics, UK)) into PC-3 cells. These were seeded in white opaque 384-well plates and grown in 10% CSS-supplemented phenol red-free RPMI 1640 for 30 hours. Cells were then treated with the indicated concentration of compound and R1881 for 16 hours. Luciferase activity was determined by adding ONE Glo (Promega, Southampton, UK) and measuring luminescence on a TopCount plate reader (Perkin-Elmer).|
|Concentrations||0.1 - 25μM|
|Incubation time||16 h|
|Animal models||LAPC-4 xenograft with male SCID mice 4–6 weeks of age|
|Formulation||0.3 % hydroxypropyl cellulose (HPC) in 0.9 % saline|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100.
Richards et al. Cancer Res. 2012 May 1;72(9):2176-82. PMID: 22411952.
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Anastrozole is a potent and highly selective aromatase (CYP19) inhibitor (IC50 = 15 nM) that has no discernible effect on adrenocorticoid hormone synthesis.
Abiraterone Acetate is an acetate salt form of Abiraterone which is a steroidal cytochrome CYP17 inhibitor with IC50 of 72 nM.
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