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 apop-tosis and block cell-cycle on HCT-116 cells. The western blotting analysis showed that CEL-2 could suppress the STAT30s 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. (c) 2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Celastrol was transformed by Streptomyces olivaceus CICC 23628, resulting in the isolation of two new friedelanes derivatives (CEL-1 and CEL-2) as metabolites. Their structures were elucidated through NMR and HR-MS analysis. In vitro studies demonstrated that CEL-2 could induce apoptosis and block the cell cycle in HCT-116 cells. Western blotting analysis showed that CEL-2 inhibited STAT3 phosphorylation and downstream gene expression. Moreover, SPR analysis confirmed the direct binding of CEL-2 with STAT3 protein. These findings suggest that CEL-2 may have potential as an anti-colorectal cancer agent by inhibiting STAT3 and inducing apoptosis and cell cycle arrest.