HDAC–Bax Multiple Ligands Enhance Bax-Dependent Apoptosis in HeLa Cells

Abstract

Inspired by the synergistic effect of BTSA1 (a Bax activator) and SAHA (a histone deacetylase (HDAC) inhibitor) in HeLa cell growth suppression, a series of novel HDAC–Bax multiple ligands were designed rationally. Compound 23, which possesses similar HDAC inhibitory activity relative to SAHA and Bax affinity comparable to BTSA1, exhibits a superior growth suppression against HeLa cells, and its antiproliferative activities are 15-fold and 3-fold higher than BTSA1 and SAHA, respectively. The better antiproliferative activity and lower cytotoxicity of compound 23 indicated that our HDAC–Bax multiple ligand design strategy achieved success. Further studies suggested that compound 23 could enhance Bax-dependent apoptosis by upregulating Bax, followed by inducing the conformational activation of Bax. To our knowledge, we first report HDAC–Bax multiple ligands and demonstrate a new paradigm for the treatment of solid tumors by enhancing Bax-dependent apoptosis.

T‐17, a novel cyclin‐dependent kinases/histone deacetylases dual inhibitor, induces cancer cells death through cell cycle arrest and apoptosis

“…Notably, the effect of T‐17 on cell apoptosis was stronger than that of SAHA and CYC202. It is well established that the Bcl‐2 family proteins are a class of proteins that involved in the process of cell apoptosis, including antiapoptotic and proapoptotic proteins (Liang et al, 2020; Tang et al, 2008; Wang et al, 2020). The expressions of apoptosis‐related proteins Bax and Bcl‐2 were examined accordingly.…”

Targeting regulated cell death pathways in acute myeloid leukemia

“…Recent findings showed direct activation of BAX by BTSA1, a pharmacological BAX activator that binds BAX with high affinity and specificity to the N-terminal activation site and induces conformational changes to BAX, leading to BAX-mediated apoptosis [ 84 ] . The histone deacetylase SAHA and its derivatives also have an affinity for BAX and induce its activation [ Table 2 ] but have not been validated in AML models [ 85 ] . Other preclinical studies suggested a mitochondrial membrane-mediated spontaneous model of BAX activation.…”

Near‐Infrared Light‐Driven Nanoparticles for Cancer Photoimmunotherapy by Synergizing Immune Cell Death and Epigenetic Regulation

“…[45] On the other hand, specific HDAC inhibitors consist of long aliphatic chains, hydrophobic recognition sites, and a zinc-binding group that is most important for the catalytic activity of HDACs. [46][47][48] Particularly, hydroxamic acid-containing HDAC inhibitors can selectively bind to Zn 2+ within the HDACs pocket to block their activity. [49][50] Herein, the hydroxamic acid structure with a long aliphatic chain was incorporated on the carboxyl group-modified Cy7-TCF molecular skeleton to synergistically achieve phototherapeutic and HDAC inhibitory effects.…”