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Review
. 2021 Sep 2:11:716830.
doi: 10.3389/fonc.2021.716830. eCollection 2021.

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

Jiacheng Lai  1 , Ziqiang Liu  1 , Yulei Zhao  1 , Chengyuan Ma  1 , Haiyan Huang  1
Affiliations
Review

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

Jiacheng Lai et al. Front Oncol. .

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.

Keywords: I-BET151; bromodomain and extra-terminal domain protein; cancer; drug combination; signal transduction.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Chemical structure of I-BET151.
Figure 2
Figure 2
I-BET151 affects the signal transduction in cancer cells and modulates critical cellular processes. I-BET151 specifically inhibits BRD2 and BRD4, decreases the intracellular content of p50/p105, diminishes the degradation of IkB-α, prevents the dissociation of p50/p105 and p65/RelA from IkB-α and their transport into the nucleus, and decreases the activity of NF-B signal transduction. In addition, I-BET151 reduces the binding of BRD4 to the Notch1 and Gli1 promoter regions, inhibits the transcription of Notch1 and Gli1, and causes the target molecules of Notch and Hh signaling pathways to change. In the aspect of influencing tumor microenvironment, I-BET151 not only targets BRD4, which leads to the increase of MICA expression and promoting NK cell degranulation, but also inhibits Stat3 signal, which leads to more CD3+ and CD8+ cells in tumors. Eventually, I-BET151 leads to cell cycle arrest, inhibition of cancer cell proliferation, stemness of stem cells, inflammatory factor release, osteoclast formation and regulation of TME.
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