New STAT3 inhibitor through biotransformation of celastrol by Streptomyces olivaceus CICC 23628

In this study, celastrol (CEL) microbial transformation was performed by Streptomyces olivaceus CICC 23628 for the first time. Two new friedelanes derivatives (CEL-1 and CEL-2) as metabolites were isolated, and their structures were elucidated based on the NMR and HR-MS analysis. Then we investigated their anti-proliferation activities in three human cancer cell lines (A549, HCT-116, HepG2) in vitro. Mechanistic studies showed that CEL-2 could induce cell apoptosis and block cell-cycle on HCT-116 cells. The western blotting analysis showed that CEL-2 could suppress the STAT3′s phosphorylation as well as its downstream genes. Furthermore, SPR analysis revealed that CEL-2 could direct bind with STAT3 protein. These studies suggest that the derivative CEL-2 may exert an anti-colorectal cancer effect via inhibiting STAT3, thereby inducing apoptosis and blocking cell-cycle. Finally, we further verified the anti-tumor effect of CEL-2 on the colorectal cancer organoid model. Our researches suggest that the biotransformation of celastrol is a potential approach to discovering new STAT3 inhibitors as anti-tumor agent.