Background: Celastrol is a bioactive compound extracted from the
root bark of “Thunder God Vine” (Tripterygium wilfordii, Hook F.) with anticancer
activities against a broad spectrum of human cancer models. This article
is aimed to review the mechanisms of action of celastrol against different
cancers, and to discuss the limitations restricting it from clinical trials as well as the potential resolutions.
Methods: MEDLINE database up to January 2015 was searched using celastrol and cancer as queries.
Results: Celastrol demonstrates efficacy against various cancers in the preclinical studies. It stabilizes the endogenous
inhibitor of NF-κB by suppressing either upstream IKK activity or downstream proteasome degradation
pathway. Celastrol inhibits Hsp90 chaperoning through disrupting Hsp90-Cdc37 interaction or inactivating
co-chaperone protein p23. It also induces UPR in proteasome-dependent or -independent manners. In
addition, Celastrol has been documented as a chemosensitizer to currently used chemotherapeutics. However,
its poor water solubility and low bioavailability as well as severe side effects have limited its clinical application.
Conclusion: Celastrol is an active natural product that exerts anti-cancer activity in a variety of cancers. It
targets multiple molecules and pathways that are essential for tumor formation and development in preclinical
setting. In spite of its remarkable pharmacological effects, celastrol is restricted from any clinical application
due to severe adverse effects and poor bioavailability. Although drug delivery systems have improved the
solubility and bioavailability, only very few drug delivery system-based cancer therapeutics have successfully
entered clinical trials. Thus, it is important to address the challenges while developing optimized delivery systems
for celastrol clinical use in the future.