Study On Antitumor Activity Of AW 01178,an Amide Class Of Small Molecule Histone Deacetylase Inhibitor

In the process of tumor metastasis,epithelial-mesenchymal transition（EMT）is often associated.EMT refers to the process by which epithelial cells alter the expression of their adhesion molecules,thereby becoming interstitial cells,which in turn gives the cells the ability to invade and migrate.EMT is divided into three types,of which type III EMT is an EMT-like process observed in cancer cells,which is related to tumor progression and metastasis,and can be defined as an EMT-like process in which cancer cells acquire interstitial features and/or lose epithelial characteristics.There are many biomarkers for EMT,such as E-cadherin belonging to cell surface proteins.E-cadherin is a single transmembrane protein.As a tumor suppressor,E-cadherin inhibits tumor formation and metastasis mainly by inhibiting cell proliferation and inducing apoptosis.In normal tissues,E-cadherin is mainly expressed in epithelial cells and plays an important role in maintaining intercellular adhesion and maintaining epithelial cell differentiation.Expression of E-cadherin is regulated by factors such as histone acetylation.Histone acetylation is a very important histone post-translational modification of the amino group of specific lysine in the tail of histones.The changes in chromatin structure and the regulation of eukaryotic gene expression are closely related.Related.When the level of histone acetylation is decreased,the affinity between histones and DNA increases,the chromatin structure tends to aggregate,and transcription is inhibited.When the level of histone acetylation increases,the affinity between histones and DNA decreases,and staining The texture structure tends to be loose and transcription is allowed to proceed.The acetylation of histones is controlled by two classes of enzymes with opposite effects:histone acetyltransferase and histone deacetylase.Many studies have shown that histone deacetylase is involved in cancer progression,tumor cell survival,metastasis,and chemoresistance.Histone deacetylases can be divided into two major classes,Zn²⁺-dependent I,II and IV,and NAD⁺-dependent Sirtuins.According to the structure,histone deacetylase inhibitors can be divided into cyclic peptides,short-chain fatty acids,hydroxamic acids,electrophilic ketones and benzamides.In the laboratory,high-throughput screening of compound libraries with E-cadherin as a marker in Hep G2 liver cancer cells was performed by In-Cell Western technology,and two compounds capable of up-regulating E-cadherin expression were obtained（laboratory numbers AC 36050 and AW 01178）.Through our research,it was found that compound AW 01178 is a new benzamide histone deacetylase inhibitor,mainly targeting class I histone deacetylase.Compound AW 01178 inhibited the proliferation of a variety of human cancer cells in vitro;in addition,compound AW 01178 also inhibited the proliferation of murine breast cancer cell 4T1.Compound AW 01178 can inhibit the metastasis of 4T1cells in vivo,while improving the survival state of mice and reducing lung and liver hemorrhage caused by tumor-bearing mice.Compound AW 01178 affects the cell cycle and promotes apoptosis.Our study found a new anti-tumor metastasis small organic molecule compound belonging to the amide histone deacetylase small molecule inhibitor.This study provides a theoretical basis for the clinical treatment of epigenetics of tumors,and provides a new epigenetic treatment strategy for cancer treatment.