Anticancer Effects of I-BET151, an Inhibitor of Bromodomain and Extra-Terminal Domain Proteins.

Jiacheng Lai,Ziqiang Liu,Yulei Zhao,Haiyan Huang,Chengyuan Ma

doi:10.3389/fonc.2021.716830

Abstract

I-BET151 is an inhibitor of bromodomain and extra-terminal domain (BET) proteins that selectively inhibits BET family members (BRD2, BRD3, BRD4, and BRDT). Over the past ten years, many studies have demonstrated the potential of I-BET151 in cancer treatment. Specifically, I-BET151 causes cell cycle arrest and inhibits tumor cell proliferation in some hematological malignancies and solid tumors, such as breast cancer, glioma, melanoma, neuroblastoma, and ovarian cancer. The anticancer activity of I-BET151 is related to its effects on NF-κB, Notch, and Hedgehog signal transduction pathway, tumor microenvironment (TME) and telomere elongation. Remarkably, the combination of I-BET151 with select anticancer drugs can partially alleviate the occurrence of drug resistance in chemotherapy. Especially, the combination of forskolin, ISX9, CHIR99021, I-BET151 and DAPT allows GBM cells to be reprogrammed into neurons, and this process does not experience an intermediate pluripotent state. The research on the anticancer mechanism of I-BET151 will lead to new treatment strategies for clinical cancer.

Highlights

Bromodomain and extra-terminal domain (BET) proteins function as epigenetic readers that mainly recognize acetylated lysine residues in chromatin proteins
This review presents a discussion of the anticancer effects and mechanisms of I-BET151, which targets BRD2 and BRD4, regulates the pathways of nuclear factor-kB (NF-kB), Notch, and Hh signal transduction, change tumor microenvironment (TME) and controls the telomere length
These I-BET151-mediated mechanisms cause the inhibition of proliferation, migration, and invasion of cancer cells, along with the induction of apoptosis

Summary

Introduction

Bromodomain and extra-terminal domain (BET) proteins function as epigenetic readers that mainly recognize acetylated lysine residues in chromatin proteins. I-BET151 targets BRD4 in multiple myeloma cells and inhibits the expression of C-MYC and IRF4, thereby improving the transcription and translation levels of MICA, promoting the degranulation of NK cells and inducing anti-tumor immune response [29].

Results

Conclusion