Effect and mechanism of novel HDAC inhibitor ZDLT-1 in colorectal cancer by regulating apoptosis and inflammation

Background: Histone deacetylase (HDAC) is a potential target for Colorectal Cancer (CRC) molecular target therapy, dehydroharmine derivative ZDLT-1 was designed to inhibit CRC cell proliferation by inhibiting HDAC target. This study aimed to explore the effect of ZDLT-1 could induce apoptosis in CRC in vitro and in vivo, and determine the mechanism of ZDLT-1. Methods: First, MTT assay, colony formation, wound healing, Transwell assay, Hoechst33342 staining and Annexin V-FITC/PI double staining assay were used to investigate the in vitro effect of ZDLT-1. Second, the toxicity and the anti-tumor effect of ZDLT-1 by subcutaneous tumorigenesis assay were used to determine the in vivo effect of ZDLT-1. In terms of mechanism, we evaluated the effect of ZDLT-1 on HDAC downstream proteins such as HIF-1 alpha, NF-kappa B, Cleaved-Caspase-3/9, GSDMD and acetylated histone by immunofluorescence and Western blot assessments. Results: This study confirmed that ZDLT-1 had anti-tumor activity by inhibiting cell proliferation in vitro and solid tumor growth in vivo. Furthermore, ZDLT-1 can inhibit CRC cell invasion, migration and apoptosis in vitro. Moreover, ZDLT-1 can promote the expression of apoptosis proteins in HIF-1 alpha/Caspase-3/Caspase-9 pathway and inhibit the expression of tumor-related immune proteins mainly in NF-kappa B/GSDMD/GSDME pathway. Conclusion: ZDLT-1 as HDAC inhibitor could suppresses CRC cell growth in vivo and in vitro by triggering HIF-1 alpha/ Caspase-3/Caspase-9 pathway in promoting apoptosis, and triggering NF-kappa B/GSDMD/GSDME pathway in inhibiting tumor inflammation. Our results propose dehydroharmine derivative ZDLT-1 as a promising therapeutic small molecular agent for CRC.