It has been demonstrated that androgen receptor (AR) plays a significant role in the progression of glioblastoma, and anti-androgen agents showed inhibitory activity with both in vitro and in vivo glioblastoma models. However, mutation of AR commonly happens in glioblastoma, which makes the anti-androgen agents less effective due to the lower binding affinity of the mutated AR to the anti-androgen drugs. Heat shock 27 kDa protein (HSP27) is a well-documented chaperone protein for AR in prostate cancer, and it chaperones AR into nucleus and also stabilizes AR. Inhibition of HSP27 results in AR degradation regardless the mutation status of AR, which makes HSP27 a good target to abolish AR in glioblastoma. We have identified a promising HSP27 inhibitor compound I that is a derivative of cyclooxygenase-2 (COX-2) inhibitor Nimesulide. It inhibits glioblastoma cell growth with IC50s around 10 nM, and does not show toxicity to mice even at 80 mg/kg which is approximately 3000 folds higher than the dose in the in vitro studies. The compound significantly induces AR degradation in multiple glioblastoma cell lines via proteasome pathway. MG132, a proteasome inhibitor could rescue the AR degradation induced by compound I. These results suggest that targeting HSP27 chaperone function to induce AR degradation in glioblastoma is a promising and novel approach.

Dual HSP27 and tubulin inhibitor abolishes androgen receptor in glioblastoma

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.