Cell lines

Human C4-2B/human THP1 cells and mouse TRAMP-C1/mouse RAW264.7 cells.

Preparation method

Soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reaction Conditions

5 μM; 3 days.

Applications

ASC-J9 suppresses macrophage recruitment and suppresses PCa invasion.

Animal models

Male 6- to 8-week-old nude mice with orthotopically xenografted 106 TRAMP-C1 cells.

Dosage form

75 mg/kg; i.p. injected three times per week for 3 weeks.

Applications

In mice, ASC-J9 significantly decreases developing distant metastatic tumors in diaphragm and lymph nodes. There are little change in mice body weight among all the mice treated.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

ASC-J9, is antitumor agent. ASC-J9 suppresses castration-resistant prostate cancer growth via degradation of full-length and splice variant androgen receptors targeting both fAR- and AR3-mediated PCa growth by ASC-J9 may represent the novel therapeutic approach to suppress castration-resistant PCa. ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor.

The androgen receptor (AR) is a type of nuclear receptor that is activated by binding either of the androgenic hormones, testosterone, or dihydrotestosterone in the cytoplasm and then translocating into the nucleus. [1]The binding of an androgen to the androgen receptor(AR) results into a conformational change, in turn, which causes dissociation of HSP, transport from the cytosol into the cell nucleus, and dimerization. The AR dimer binds to a specific sequence of DNA known as HRE which can interact with other proteins in the nucleus, leading to up-regulation or down-regulation of specific gene transcription.[2]

ASC-J9, the AR degradation enhancer, suppressed both macrophage migration and subsequent PCa cell invasion. Additionally, ASC-J9 can regulate pSTAT3-CCL2 signaling using two pathways: an AR-dependent pathway via inhibiting PIAS3 expression and an AR-independent pathway via direct inhibition of the STAT3 phosphorylation/activation through mouse model in vivo with orthotopically injected TRAMP-C1 cells. In conclusion,a new and better therapeutic strategies using ASC-J9 alone or a combinational therapy that simultaneously targets androgens/AR signaling and PIAS3-pSTAT3-CCL2 signaling to better battle PCa growth and metastasis at castration-resistant stage.[3]

References:

1. Lu NZ. et al. "International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors". Pharmacol. Rev. 2006, 58 (4): 782–97.

2. Heemers HV, Tindall DJ. "Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex". Endocr. Rev. 2007, 28 (7): 778–808.

3. Lin TH. et al. “Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 (Enzalutamide) or Casodex (Bicalutamide) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling.” Cell Death

Dis. 2013,4:e764