| Autor: |
Yongsheng Ruan, Hye Na Kim, Heather A. Ogana, Zesheng Wan, Samantha Hurwitz, Cydney Nichols, Nour Abdel-Azim, Ariana Coba, Seyoung Seo, Yong-Hwee Eddie Loh, Eun Ji Gang, Hisham Abdel-Azim, Chih-Lin Hsieh, Michael R. Lieber, Chintan Parekh, Dhananjaya Pal, Deepa Bhojwani, Donald L. Durden, Yong-Mi Kim |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Frontiers in Oncology, Vol 11 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2234-943X |
| DOI: |
10.3389/fonc.2021.766888 |
| Popis: |
The PI3K/Akt pathway—and in particular PI3Kδ—is known for its role in drug resistant B-cell acute lymphoblastic leukemia (B-ALL) and it is often upregulated in refractory or relapsed B-ALL. Myc proteins are transcription factors responsible for transcribing pro-proliferative genes and c-Myc is often overexpressed in cancers. The chromatin regulator BRD4 is required for expression of c-Myc in hematologic malignancies including B-ALL. Previously, combination of BRD4 and PI3K inhibition with SF2523 was shown to successfully decrease Myc expression. However, the underlying mechanism and effect of dual inhibition of PI3Kδ/BRD4 in B-ALL remains unknown. To study this, we utilized SF2535, a novel small molecule dual inhibitor which can specifically target the PI3Kδ isoform and BRD4. We treated primary B-ALL cells with various concentrations of SF2535 and studied its effect on specific pharmacological on-target mechanisms such as apoptosis, cell cycle, cell proliferation, and adhesion molecules expression usingin vitro and in vivo models. SF2535 significantly downregulates both c-Myc mRNA and protein expression through inhibition of BRD4 at the c-Myc promoter site and decreases p-AKT expression through inhibition of the PI3Kδ/AKT pathway. SF2535 induced apoptosis in B-ALL by downregulation of BCL-2 and increased cleavage of caspase-3, caspase-7, and PARP. Moreover, SF2535 induced cell cycle arrest and decreased cell counts in B-ALL. Interestingly, SF2535 decreased the mean fluorescence intensity (MFI) of integrin α4, α5, α6, and β1 while increasing MFI of CXCR4, indicating that SF2535 may work through inside-out signaling of integrins. Taken together, our data provide a rationale for the clinical evaluation of targeting PI3Kδ/BRD4 in refractory or relapsed B-ALL using SF2535. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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